|
1
|
Wan Z, Yuan M, Liu Z, Cai Y, He H, Hao K. Impact of Dapagliflozin on Hepatic Lipid Metabolism and a Dynamic Model of Ketone Body Levels. AAPS J 2025; 27:38. [PMID: 39900889 DOI: 10.1208/s12248-025-01024-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2024] [Accepted: 01/15/2025] [Indexed: 02/05/2025] Open
Abstract
The rising prevalence of metabolic-associated steatotic liver disease emphasizes the need to understand its lipid metabolism. Dapagliflozin may improve hepatic steatosis but could also increase the risk of ketoacidosis by elevating β-hydroxybutyrate (KB) levels. This study investigates dapagliflozin's effects on hepatic lipid metabolism and quantifies KB levels in vivo. Male Sprague-Dawley rats were fed either a normal diet or a high-fat diet (HFD) for 12 weeks. The HFD rats were then divided into four subgroups to receive vehicle, 0.5 mg/kg, 1 mg/kg, and 3 mg/kg of dapagliflozin for four weeks. Free fatty acids (FFA) and KB levels were monitored, while protein and gene expression were analyzed. And a dynamic model of KB was developed for humans based on preclinical data. Dapagliflozin decreased body weight and visceral fat in HFD rats, increasing KB by upregulating CPT1a, HMGCS2, and HMGCL, and downregulating ACC. These changes correlated with reduced liver/fat index, liver pathology score, and oil-red staining area. A pharmacokinetic/pharmacodynamic (PK/PD) model was created from preclinical data to quantify KB levels in rats and validated in humans. Dapagliflozin reduces hepatic steatosis by enhancing fatty acid β-oxidation and ketogenesis and inhibiting fat synthesis. A dynamic model accurately predicts ketone body levels in treated individuals.
Collapse
Affiliation(s)
- Zhijie Wan
- State Key Laboratory of Natural Medicine, Jiangsu Province Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, 210009, China
| | - Ming Yuan
- Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, 210009, China
| | - Ziao Liu
- State Key Laboratory of Natural Medicine, Jiangsu Province Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, 210009, China
| | - Yuan Cai
- Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, 210009, China
| | - Hua He
- Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, 210009, China.
| | - Kun Hao
- State Key Laboratory of Natural Medicine, Jiangsu Province Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, 210009, China.
| |
Collapse
|
|
2
|
Yang L, Wang F, Liu S, Xian Z, Yang S, Xu Y, Shu L, Yan X, He J, Li X, Peng C, Bi C, Yuan Y, Chen S, Han L, Yang R, Li Y. Unique metabolomics characteristics for distinguishing cirrhosis related to different liver diseases: A systematic review and meta-analysis. Diabetes Metab Syndr 2024; 18:103068. [PMID: 38959546 DOI: 10.1016/j.dsx.2024.103068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Revised: 05/24/2024] [Accepted: 06/28/2024] [Indexed: 07/05/2024]
Abstract
BACKGROUND AND AIM Clinical evidence for early identification and diagnosis of liver cirrhosis (LC) caused by different types of liver disease is limited. We investigated this topic through a meta-analysis of quantitative metabolomics. METHODS Four databases were searched until October 31, 2022 for studies comparing metabolite levels between patients with different types of liver disease and control individuals. A random-effects model was applied for the meta-analysis. RESULTS This study included 55 studies with 8266 clinical participants, covering 348 metabolites. In LC related to drug-induced liver injury (DILI), hepatitis B virus (HBV) infection, and non-alcoholic fatty liver disease (NAFLD), the primary bile acid biosynthesis (taurocholic acid: SMD, 1.08[0.81, 1.35]; P < 0.00001; glycocholic acid: SMD, 1.35[1.07, 1.62]; P < 0.00001; taurochenodeoxycholic acid: SMD, 1.36[0.94, 1.78]; P < 0.00001; glycochenodeoxycholic acid: SMD, 1.49[0.93, 2.06]; P < 0.00001), proline and arginine (l-proline: SMD, 1.06[0.53, 1.58]; P < 0.0001; hydroxyproline: SMD, 0.81[0.30, 1.33]; P = 0.002), and fatty acid biosynthesis (palmitic acid: SMD, 0.44[0.21, 0.67]; P = 0.0002; oleic acid: SMD, 0.46[0.19, 0.73]; P = 0.0008; stearic acid: SMD, 0.37[0.07, 0.68]; P = 0.02) metabolic pathways were significantly altered. CONCLUSION We identified key biomarkers and metabolic characteristics for distinguishing and identifying LC related to different types of liver disease, providing a new perspective for early diagnosis, disease monitoring, and precise treatment.
Collapse
Affiliation(s)
- Liu Yang
- School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Fang Wang
- School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Sijia Liu
- School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Zicheng Xian
- School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Shenshen Yang
- School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Yanyan Xu
- School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Lexin Shu
- School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Xingxu Yan
- School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Junjie He
- School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Xia Li
- School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Cheng Peng
- School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Chenghao Bi
- School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Yu Yuan
- School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Siyu Chen
- School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Liwen Han
- Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, 250117, China.
| | - Rongrong Yang
- Public Health Science and Engineering College, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China.
| | - Yubo Li
- School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China; State Key Laboratory of Component-based Chinese Medicine, Haihe Laboratory of Modern Chinese Medicine, Tianjin, 301617, China.
| |
Collapse
|
|
3
|
Moore MP, Shryack G, Alessi I, Wieschhaus N, Meers GM, Johnson SA, Wheeler AA, Ibdah JA, Parks EJ, Rector RS. Relationship between serum β-hydroxybutyrate and hepatic fatty acid oxidation in individuals with obesity and NAFLD. Am J Physiol Endocrinol Metab 2024; 326:E493-E502. [PMID: 38381399 PMCID: PMC11194052 DOI: 10.1152/ajpendo.00336.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Revised: 02/15/2024] [Accepted: 02/16/2024] [Indexed: 02/22/2024]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is characterized by excess lipid accumulation that can progress to inflammation (nonalcoholic steatohepatitis, NASH), and fibrosis. Serum β-hydroxybutyrate (β-HB), a product of the ketogenic pathway, is commonly used as a surrogate marker for hepatic fatty acid oxidation (FAO). However, it remains uncertain whether this relationship holds true in the context of NAFLD in humans. We compared fasting serum β-HB levels with direct measurement of liver mitochondrial palmitate oxidation in humans stratified based on NAFLD severity (n = 142). Patients were stratified based on NAFLD activity score (NAS): NAS = 0 (no disease), NAS = 1-2 (mild), NAS = 3-4 (moderate), and NAS ≥ 5 (advanced). Moderate and advanced NAFLD is associated with reductions in liver 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), serum β-HB, but not 3-hydroxy-3-methylglutaryl-CoA lyase (HMGCL) mRNA, relative to no disease. Worsening liver mitochondrial complete palmitate oxidation corresponded with lower HMGCS2 mRNA but not total (complete + incomplete) palmitate oxidation. Interestingly, we found that liver HMGCS2 mRNA and serum β-HB correlated with liver mitochondrial β-hydroxyacyl-CoA dehydrogenase (β-HAD) activity and CPT1A mRNA. Also, lower mitochondrial mass and markers of mitochondrial turnover positively correlated with lower HMGCS2 in the liver. These data suggest that liver ketogenesis and FAO occur at comparable rates in individuals with NAFLD. Our findings support the utility of serum β-HB to serve as a marker of liver injury and hepatic FAO in the context of NAFLD.NEW & NOTEWORTHY Serum β-hydroxybutyrate (β-HB) is frequently utilized as a surrogate marker for hepatic fatty acid oxidation; however, few studies have investigated this relationship during states of liver disease. We found that the progression of nonalcoholic fatty liver disease (NAFLD) is associated with reductions in circulating β-HB and liver 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2). As well, decreased rates of hepatic fatty acid oxidation correlated with liver HMGCS2 mRNA and serum β-HB. Our work supports serum β-HB as a potential marker for hepatic fatty acid oxidation and liver injury during NAFLD.
Collapse
Affiliation(s)
- Mary P Moore
- Research Service, Harry S Truman Memorial Veterans Medical Center, Columbia, Missouri, United States
- Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, Missouri, United States
| | - Grace Shryack
- Research Service, Harry S Truman Memorial Veterans Medical Center, Columbia, Missouri, United States
- Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, Missouri, United States
- NextGen Precision Health, Columbia, Missouri, United States
| | - Isabella Alessi
- Research Service, Harry S Truman Memorial Veterans Medical Center, Columbia, Missouri, United States
- Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, Missouri, United States
- NextGen Precision Health, Columbia, Missouri, United States
| | - Nicole Wieschhaus
- Research Service, Harry S Truman Memorial Veterans Medical Center, Columbia, Missouri, United States
- Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, Missouri, United States
- NextGen Precision Health, Columbia, Missouri, United States
| | - Grace M Meers
- Research Service, Harry S Truman Memorial Veterans Medical Center, Columbia, Missouri, United States
- Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, Missouri, United States
- NextGen Precision Health, Columbia, Missouri, United States
| | - Sarah A Johnson
- Research Service, Harry S Truman Memorial Veterans Medical Center, Columbia, Missouri, United States
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Missouri, Columbia, Missouri, United States
| | - Andrew A Wheeler
- Department of Surgery, University of Missouri, Columbia, Missouri, United States
| | - Jamal A Ibdah
- Research Service, Harry S Truman Memorial Veterans Medical Center, Columbia, Missouri, United States
- Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, Missouri, United States
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Missouri, Columbia, Missouri, United States
| | - Elizabeth J Parks
- Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, Missouri, United States
- NextGen Precision Health, Columbia, Missouri, United States
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Missouri, Columbia, Missouri, United States
| | - R Scott Rector
- Research Service, Harry S Truman Memorial Veterans Medical Center, Columbia, Missouri, United States
- Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, Missouri, United States
- NextGen Precision Health, Columbia, Missouri, United States
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Missouri, Columbia, Missouri, United States
| |
Collapse
|
|
4
|
Li K, Wang WH, Wu JB, Xiao WH. β-hydroxybutyrate: A crucial therapeutic target for diverse liver diseases. Biomed Pharmacother 2023; 165:115191. [PMID: 37487440 DOI: 10.1016/j.biopha.2023.115191] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Revised: 07/13/2023] [Accepted: 07/18/2023] [Indexed: 07/26/2023] Open
Abstract
β-hydroxybutyrate (β-HB), the most abundant ketone body, is produced primarily in the liver and acts as a substitute energy fuel to provide energy to extrahepatic tissues in the event of hypoglycemia or glycogen depletion. We now have an improved understanding of β-HB as a signal molecule and epigenetic regulatory factor as a result of intensive research over the last ten years. Because β-HB regulates various physiological and pathological processes, it may have a potential role in the treatment of metabolic diseases. The liver is the most significant metabolic organ, and the part that β-HB plays in liver disorders is receiving increasing attention. In this review, we summarize the therapeutic effects of β-HB on liver diseases and its underlying mechanisms of action. Moreover, we explore the prospects of exogenous supplements and endogenous ketosis including fasting, caloric restriction (CR), ketogenic diet (KD), and exercise as adjuvant nutritional therapies to protect the liver from damage and provide insights and strategies for exploring the treatment of various liver diseases.
Collapse
Affiliation(s)
- Ke Li
- Key Lab of Exercise and Health Sciences of Ministry of Education, Shanghai University of Sport, Shanghai 200438, China; Shanghai Key Lab of Human Performance, Shanghai University of Sport, Shanghai 200438, China
| | - Wen-Hong Wang
- Key Lab of Exercise and Health Sciences of Ministry of Education, Shanghai University of Sport, Shanghai 200438, China; Shanghai Key Lab of Human Performance, Shanghai University of Sport, Shanghai 200438, China
| | - Jia-Bin Wu
- Key Lab of Exercise and Health Sciences of Ministry of Education, Shanghai University of Sport, Shanghai 200438, China; Shanghai Key Lab of Human Performance, Shanghai University of Sport, Shanghai 200438, China
| | - Wei-Hua Xiao
- Key Lab of Exercise and Health Sciences of Ministry of Education, Shanghai University of Sport, Shanghai 200438, China; Shanghai Key Lab of Human Performance, Shanghai University of Sport, Shanghai 200438, China.
| |
Collapse
|
|
5
|
Jamshidi N, Feizi A, Sirlin CB, Lavine JE, Kuo MD. Multi-Modality, Multi-Dimensional Characterization of Pediatric Non-Alcoholic Fatty Liver Disease. Metabolites 2023; 13:929. [PMID: 37623872 PMCID: PMC10456937 DOI: 10.3390/metabo13080929] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Revised: 07/29/2023] [Accepted: 08/02/2023] [Indexed: 08/26/2023] Open
Abstract
Non-alcoholic fatty liver disease is a multifaceted disease that progresses through multiple phases; it involves metabolic as well as structural changes. These alterations can be measured directly or indirectly through blood, non-invasive imaging, and/or tissue analyses. While some studies have evaluated the correlations between two sets of measurements (e.g., histopathology with cross-sectional imaging or blood biomarkers), the interrelationships, if any, among histopathology, clinical blood profiles, cross-sectional imaging, and metabolomics in a pediatric cohort remain unknown. We created a multiparametric clinical MRI-histopathologic NMR network map of pediatric NAFLD through multimodal correlation networks, in order to gain insight into how these different sets of measurements are related. We found that leptin and other blood markers were correlated with many other measurements; however, upon filtering out the blood biomarkers, the network was decomposed into three independent hubs centered around histopathological features, each with associated MRI and plasma metabolites. These multi-modality maps could serve as a framework for characterizing disease status and progression and could potentially guide medical interventions.
Collapse
Affiliation(s)
- Neema Jamshidi
- Department of Radiological Sciences, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
| | - Alborz Feizi
- School of Medicine, Yale University, New Haven, CT 06520, USA
| | - Claude B. Sirlin
- Department of Radiology, University of California, San Diego, CA 92093, USA
| | - Joel E. Lavine
- Department of Pediatrics, Columbia University, New York, NY 10027, USA
| | - Michael D. Kuo
- Medical AI Laboratory Program, The University of Hong Kong, Hong Kong SAR, China
| |
Collapse
|
|
6
|
Ramakrishnan S, Mooli RGR, Han Y, Fiorenza E, Kumar S, Bello F, Nallanagulagari A, Karra S, Teng L, Jurczak M. Hepatic ketogenesis regulates lipid homeostasis via ACSL1-mediated fatty acid partitioning. RESEARCH SQUARE 2023:rs.3.rs-3147009. [PMID: 37503004 PMCID: PMC10371136 DOI: 10.21203/rs.3.rs-3147009/v1] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/29/2023]
Abstract
Liver-derived ketone bodies play a crucial role in fasting energy homeostasis by fueling the brain and peripheral tissues. Ketogenesis also acts as a conduit to remove excess acetyl-CoA generated from fatty acid oxidation and protects against diet-induced hepatic steatosis. Surprisingly, no study has examined the role of ketogenesis in fasting-associated hepatocellular lipid metabolism. Ketogenesis is driven by the rate-limiting mitochondrial enzyme 3-hydroxymethylglutaryl CoA synthase (HMGCS2) abundantly expressed in the liver. Here, we show that ketogenic insufficiency via disruption of hepatic HMGCS2 exacerbates liver steatosis in fasted chow and high-fat-fed mice. We found that the hepatic steatosis is driven by increased fatty acid partitioning to the endoplasmic reticulum (ER) for re-esterification via acyl-CoA synthetase long-chain family member 1 (ACSL1). Mechanistically, acetyl-CoA accumulation from impaired hepatic ketogenesis is responsible for the elevated translocation of ACSL1 to the ER. Moreover, we show increased ER-localized ACSL1 and re-esterification of lipids in human NASH displaying impaired hepatic ketogenesis. Finally, we show that L-carnitine, which buffers excess acetyl-CoA, decreases the ER-associated ACSL1 and alleviates hepatic steatosis. Thus, ketogenesis via controlling hepatocellular acetyl-CoA homeostasis regulates lipid partitioning and protects against hepatic steatosis.
Collapse
|
|
7
|
Darci-Maher N, Alvarez M, Arasu UT, Selvarajan I, Lee SHT, Pan DZ, Miao Z, Das SS, Kaminska D, Örd T, Benhammou JN, Wabitsch M, Pisegna JR, Männistö V, Pietiläinen KH, Laakso M, Sinsheimer JS, Kaikkonen MU, Pihlajamäki J, Pajukanta P. Cross-tissue omics analysis discovers ten adipose genes encoding secreted proteins in obesity-related non-alcoholic fatty liver disease. EBioMedicine 2023; 92:104620. [PMID: 37224770 PMCID: PMC10277924 DOI: 10.1016/j.ebiom.2023.104620] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Revised: 04/14/2023] [Accepted: 05/03/2023] [Indexed: 05/26/2023] Open
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is a fast-growing, underdiagnosed, epidemic. We hypothesise that obesity-related inflammation compromises adipose tissue functions, preventing efficient fat storage, and thus driving ectopic fat accumulation into the liver. METHODS To identify adipose-based mechanisms and potential serum biomarker candidates (SBCs) for NAFLD, we utilise dual-tissue RNA-sequencing (RNA-seq) data in adipose tissue and liver, paired with histology-based NAFLD diagnosis, from the same individuals in a cohort of obese individuals. We first scan for genes that are differentially expressed (DE) for NAFLD in obese individuals' subcutaneous adipose tissue but not in their liver; encode proteins secreted to serum; and show preferential adipose expression. Then the identified genes are filtered to key adipose-origin NAFLD genes by best subset analysis, knockdown experiments during human preadipocyte differentiation, recombinant protein treatment experiments in human liver HepG2 cells, and genetic analysis. FINDINGS We discover a set of genes, including 10 SBCs, that may modulate NAFLD pathogenesis by impacting adipose tissue function. Based on best subset analysis, we further follow-up on two SBCs CCDC80 and SOD3 by knockdown in human preadipocytes and subsequent differentiation experiments, which show that they modulate crucial adipogenesis genes, LPL, SREBPF1, and LEP. We also show that treatment of the liver HepG2 cells with the CCDC80 and SOD3 recombinant proteins impacts genes related to steatosis and lipid processing, including PPARA, NFE2L2, and RNF128. Finally, utilizing the adipose NAFLD DE gene cis-regulatory variants associated with serum triglycerides (TGs) in extensive genome-wide association studies (GWASs), we demonstrate a unidirectional effect of serum TGs on NAFLD with Mendelian Randomization (MR) analysis. We also demonstrate that a single SNP regulating one of the SBC genes, rs2845885, produces a significant MR result by itself. This supports the conclusion that genetically regulated adipose expression of the NAFLD DE genes may contribute to NAFLD through changes in serum TG levels. INTERPRETATION Our results from the dual-tissue transcriptomics screening improve the understanding of obesity-related NAFLD by providing a targeted set of 10 adipose tissue-active genes as new serum biomarker candidates for the currently grossly underdiagnosed fatty liver disease. FUNDING The work was supported by NIH grants R01HG010505 and R01DK132775. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. The KOBS study (J. P.) was supported by the Finnish Diabetes Research Foundation, Kuopio University Hospital Project grant (EVO/VTR grants 2005-2019), and the Academy of Finland grant (Contract no. 138006). This study was funded by the European Research Council under the European Union's Horizon 2020 research and innovation program (Grant No. 802825 to M. U. K.). K. H. P. was funded by the Academy of Finland (grant numbers 272376, 266286, 314383, and 335443), the Finnish Medical Foundation, Gyllenberg Foundation, Novo Nordisk Foundation (grant numbers NNF10OC1013354, NNF17OC0027232, and NNF20OC0060547), Finnish Diabetes Research Foundation, Finnish Foundation for Cardiovascular Research, University of Helsinki, and Helsinki University Hospital and Government Research Funds. I. S. was funded by the Instrumentarium Science Foundation. Personal grants to U. T. A. were received from the Matti and Vappu Maukonen Foundation, Ella och Georg Ehrnrooths Stiftelse and the Finnish Foundation for Cardiovascular Research.
Collapse
Affiliation(s)
- Nicholas Darci-Maher
- Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, USA
| | - Marcus Alvarez
- Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, USA
| | - Uma Thanigai Arasu
- A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
| | - Ilakya Selvarajan
- A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
| | - Seung Hyuk T Lee
- Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, USA
| | - David Z Pan
- Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, USA
| | - Zong Miao
- Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, USA
| | - Sankha Subhra Das
- Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, USA
| | - Dorota Kaminska
- Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, USA; Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland; Division of Cardiology, David Geffen School of Medicine at UCLA, Los Angeles, USA
| | - Tiit Örd
- A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
| | - Jihane N Benhammou
- Vatche and Tamar Manoukian Division of Digestive Diseases, and Gastroenterology, Hepatology and Parenteral Nutrition, David Geffen School of Medicine at UCLA and VA Greater Los Angeles HCS, Los Angeles, USA
| | - Martin Wabitsch
- Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics and Adolescent Medicine, University of Ulm, Ulm, Germany
| | - Joseph R Pisegna
- Department of Medicine and Human Genetics, Division of Gastroenterology, Hepatology and Parenteral Nutrition, David Geffen School of Medicine at UCLA and VA Greater Los Angeles HCS, Los Angeles, USA
| | - Ville Männistö
- Department of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland
| | - Kirsi H Pietiläinen
- Obesity Research Unit, Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland; Obesity Center, Abdominal Center, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Markku Laakso
- Institute of Clinical Medicine, Kuopio University Hospital, University of Eastern Finland, Kuopio, Finland
| | - Janet S Sinsheimer
- Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, USA; Department of Biostatistics, UCLA Fielding School of Public Health, Los Angeles, USA; Department of Computational Medicine, David Geffen School of Medicine at UCLA, Los Angeles, USA
| | - Minna U Kaikkonen
- A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
| | - Jussi Pihlajamäki
- Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland; Department of Medicine, Endocrinology and Clinical Nutrition, Kuopio University Hospital, Kuopio, Finland
| | - Päivi Pajukanta
- Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, USA; Bioinformatics Interdepartmental Program, UCLA, Los Angeles, USA; Institute for Precision Health, David Geffen School of Medicine at UCLA, Los Angeles, USA.
| |
Collapse
|
|
8
|
Gutiérrez-Cuevas J, Lucano-Landeros S, López-Cifuentes D, Santos A, Armendariz-Borunda J. Epidemiologic, Genetic, Pathogenic, Metabolic, Epigenetic Aspects Involved in NASH-HCC: Current Therapeutic Strategies. Cancers (Basel) 2022; 15:23. [PMID: 36612019 PMCID: PMC9818030 DOI: 10.3390/cancers15010023] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 12/12/2022] [Accepted: 12/14/2022] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver cancer and is the sixth most frequent cancer in the world, being the third cause of cancer-related deaths. Nonalcoholic steatohepatitis (NASH) is characterized by fatty infiltration, oxidative stress and necroinflammation of the liver, with or without fibrosis, which can progress to advanced liver fibrosis, cirrhosis and HCC. Obesity, metabolic syndrome, insulin resistance, and diabetes exacerbates the course of NASH, which elevate the risk of HCC. The growing prevalence of obesity are related with increasing incidence of NASH, which may play a growing role in HCC epidemiology worldwide. In addition, HCC initiation and progression is driven by reprogramming of metabolism, which indicates growing appreciation of metabolism in the pathogenesis of this disease. Although no specific preventive pharmacological treatments have recommended for NASH, dietary restriction and exercise are recommended. This review focuses on the molecular connections between HCC and NASH, including genetic and risk factors, highlighting the metabolic reprogramming and aberrant epigenetic alterations in the development of HCC in NASH. Current therapeutic aspects of NASH/HCC are also reviewed.
Collapse
Affiliation(s)
- Jorge Gutiérrez-Cuevas
- Department of Molecular Biology and Genomics, Institute for Molecular Biology in Medicine and Gene Therapy, University of Guadalajara, CUCS, Guadalajara 44340, Jalisco, Mexico
| | - Silvia Lucano-Landeros
- Department of Molecular Biology and Genomics, Institute for Molecular Biology in Medicine and Gene Therapy, University of Guadalajara, CUCS, Guadalajara 44340, Jalisco, Mexico
| | - Daniel López-Cifuentes
- Department of Molecular Biology and Genomics, Institute for Molecular Biology in Medicine and Gene Therapy, University of Guadalajara, CUCS, Guadalajara 44340, Jalisco, Mexico
| | - Arturo Santos
- Tecnologico de Monterrey, EMCS, Campus Guadalajara, Zapopan 45201, Jalisco, Mexico
| | - Juan Armendariz-Borunda
- Department of Molecular Biology and Genomics, Institute for Molecular Biology in Medicine and Gene Therapy, University of Guadalajara, CUCS, Guadalajara 44340, Jalisco, Mexico
- Tecnologico de Monterrey, EMCS, Campus Guadalajara, Zapopan 45201, Jalisco, Mexico
| |
Collapse
|
|
9
|
Mokhtari Z, Hosseini E, Hekmatdoost A, Haskey N, Gibson DL, Askari G. The effects of fasting diets on nonalcoholic fatty liver disease. Nutr Rev 2022:6809036. [DOI: 10.1093/nutrit/nuac092] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in the world. There is no confirmed treatment for NAFLD as yet. Recently, fasting regimens and their relationship to NAFLD have drawn a great deal of attention in the literature. We review the current evidence that supports fasting diets as an adjunctive therapeutic strategy for patients with NAFLD and address potential action mechanisms. We reason that the fasting diets might be a promising approach for modulating hepatic steatosis, fibroblast growth factors 19 and 21 signaling, lipophagy, and the metabolic profile.
Collapse
Affiliation(s)
- Zeinab Mokhtari
- Nutrition and Food Security Research Center, Isfahan University of Medical Sciences are with the , Isfahan, Iran
| | - Elham Hosseini
- Nutrition and Food Security Research Center, Isfahan University of Medical Sciences are with the , Isfahan, Iran
| | - Azita Hekmatdoost
- Department of Clinical Nutrition and Dietetics, Faculty of Nutrition Sciences and, Food Technology, National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Sciences with the , Tehran, Iran
| | - Natasha Haskey
- Department of Biology, University of British Columbia—Okanagan Campus are with the , Kelowna, British Columbia, Canada
| | - Deanna L Gibson
- Department of Biology, University of British Columbia—Okanagan Campus are with the , Kelowna, British Columbia, Canada
| | - Gholamreza Askari
- Nutrition and Food Security Research Center, Isfahan University of Medical Sciences are with the , Isfahan, Iran
- Department of Community Nutrition, School of Nutrition and Food Science, Isfahan University of Medical Sciences with the , Isfahan, Iran
| |
Collapse
|
|
10
|
Hughey CC, Puchalska P, Crawford PA. Integrating the contributions of mitochondrial oxidative metabolism to lipotoxicity and inflammation in NAFLD pathogenesis. Biochim Biophys Acta Mol Cell Biol Lipids 2022; 1867:159209. [DOI: 10.1016/j.bbalip.2022.159209] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Revised: 06/25/2022] [Accepted: 07/27/2022] [Indexed: 11/28/2022]
|
|
11
|
Mooli RGR, Ramakrishnan SK. Emerging Role of Hepatic Ketogenesis in Fatty Liver Disease. Front Physiol 2022; 13:946474. [PMID: 35860662 PMCID: PMC9289363 DOI: 10.3389/fphys.2022.946474] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Accepted: 06/08/2022] [Indexed: 11/18/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD), the most common chronic liver diseases, arise from non-alcoholic fatty liver (NAFL) characterized by excessive fat accumulation as triglycerides. Although NAFL is benign, it could progress to non-alcoholic steatohepatitis (NASH) manifested with inflammation, hepatocyte damage and fibrosis. A subset of NASH patients develops end-stage liver diseases such as cirrhosis and hepatocellular carcinoma. The pathogenesis of NAFLD is highly complex and strongly associated with perturbations in lipid and glucose metabolism. Lipid disposal pathways, in particular, impairment in condensation of acetyl-CoA derived from β-oxidation into ketogenic pathway strongly influence the hepatic lipid loads and glucose metabolism. Current evidence suggests that ketogenesis dispose up to two-thirds of the lipids entering the liver, and its dysregulation significantly contribute to the NAFLD pathogenesis. Moreover, ketone body administration in mice and humans shows a significant improvement in NAFLD. This review focuses on hepatic ketogenesis and its role in NAFLD pathogenesis. We review the possible mechanisms through which impaired hepatic ketogenesis may promote NAFLD progression. Finally, the review sheds light on the therapeutic implications of a ketogenic diet in NAFLD.
Collapse
|
|
12
|
Lo EKK, Felicianna, Xu JH, Zhan Q, Zeng Z, El-Nezami H. The Emerging Role of Branched-Chain Amino Acids in Liver Diseases. Biomedicines 2022; 10:1444. [PMID: 35740464 PMCID: PMC9220261 DOI: 10.3390/biomedicines10061444] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 06/07/2022] [Accepted: 06/16/2022] [Indexed: 02/06/2023] Open
Abstract
Chronic liver diseases pose a substantial health burden worldwide, with approximately two million deaths each year. Branched-chain amino acids (BCAAs)-valine, leucine, and isoleucine-are a group of essential amino acids that are essential for human health. Despite the necessity of a dietary intake of BCAA, emerging data indicate the undeniable correlation between elevated circulating BCAA levels and chronic liver diseases, including non-alcoholic fatty liver diseases (NAFLD), cirrhosis, and hepatocellular carcinoma (HCC). Moreover, circulatory BCAAs were positively associated with a higher cholesterol level, liver fat content, and insulin resistance (IR). However, BCAA supplementation was found to provide positive outcomes in cirrhosis and HCC patients. This review will attempt to address the contradictory claims found in the literature, with a special focus on BCAAs' distribution, key signaling pathways, and the modulation of gut microbiota. This should provide a better understanding of BCAAs' possible contribution to liver health.
Collapse
Affiliation(s)
- Emily Kwun Kwan Lo
- School of Biological Sciences, University of Hong Kong, Pokfulam, Hong Kong 999077, China; (E.K.K.L.); (F.)
| | - Felicianna
- School of Biological Sciences, University of Hong Kong, Pokfulam, Hong Kong 999077, China; (E.K.K.L.); (F.)
| | - Jing-Hang Xu
- Department of Infectious Diseases, Peking University First Hospital, Peking University, Beijing 100034, China; (J.-H.X.); (Q.Z.)
| | - Qiao Zhan
- Department of Infectious Diseases, Peking University First Hospital, Peking University, Beijing 100034, China; (J.-H.X.); (Q.Z.)
| | - Zheng Zeng
- Department of Infectious Diseases, Peking University First Hospital, Peking University, Beijing 100034, China; (J.-H.X.); (Q.Z.)
| | - Hani El-Nezami
- School of Biological Sciences, University of Hong Kong, Pokfulam, Hong Kong 999077, China; (E.K.K.L.); (F.)
- Institute of Public Health and Clinical Nutrition, School of Medicine, University of Eastern Finland, FI-70211 Kuopio, Finland
| |
Collapse
|
|
13
|
Asif S, Kim RY, Fatica T, Sim J, Zhao X, Oh Y, Denoncourt A, Cheung A, Downey M, Mulvihill EE, Kim KH. Hmgcs2-mediated ketogenesis modulates high-fat diet-induced hepatosteatosis. Mol Metab 2022; 61:101494. [PMID: 35421611 PMCID: PMC9039870 DOI: 10.1016/j.molmet.2022.101494] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 04/01/2022] [Accepted: 04/04/2022] [Indexed: 12/11/2022] Open
Abstract
OBJECTIVE Aberrant ketogenesis is correlated with the degree of steatosis in NAFLD patients, and an inborn error of ketogenesis (mitochondrial HMG-CoA synthase deficiency) is commonly associated with the development of the fatty liver. Here we aimed to determine the impact of Hmgcs2-mediated ketogenesis and its modulations on the development and treatment of fatty liver disease. METHODS Loss- and gain-of-ketogenic function through in vivo and in vitro models, achieved by Hmgcs2 knockout and overexpression, respectively, were examined to investigate the role of ketogenesis in the hepatic lipid accumulation during neonatal development and the diet-induced NAFLD mouse model. RESULTS Ketogenic function was decreased in NAFLD mice with a reduction in Hmgcs2 expression. Mice lacking Hmgcs2 developed spontaneous fatty liver phenotype during postnatal development, which was rescued by a shift to a low-fat dietary composition via early weaning. Hmgcs2 heterozygous mice, which exhibited reduced ketogenic activity, were more susceptible to diet-induced NAFLD development, whereas HMGCS2 overexpression in NAFLD mice improved hepatosteatosis and glucose homeostasis. CONCLUSIONS Our study adds new knowledge to the field of ketone body metabolism and shows that Hmgcs2-mediated ketogenesis modulates hepatic lipid regulation under a fat-enriched nutritional environment. The regulation of hepatic ketogenesis may be a viable therapeutic strategy in the prevention and treatment of hepatosteatosis.
Collapse
Affiliation(s)
- Shaza Asif
- University of Ottawa Heart Institute, Ottawa, ON, K1Y 4W7, Canada; Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON, K1H 8M5, Canada
| | - Ri Youn Kim
- University of Ottawa Heart Institute, Ottawa, ON, K1Y 4W7, Canada
| | - Thet Fatica
- University of Ottawa Heart Institute, Ottawa, ON, K1Y 4W7, Canada
| | - Jordan Sim
- Department of Pathology and Laboratory Medicine, The Ottawa Hospital, Ottawa, ON, K1H 8M5, Canada
| | - Xiaoling Zhao
- University of Ottawa Heart Institute, Ottawa, ON, K1Y 4W7, Canada
| | - Yena Oh
- University of Ottawa Heart Institute, Ottawa, ON, K1Y 4W7, Canada; Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON, K1H 8M5, Canada
| | - Alix Denoncourt
- Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON, K1H 8M5, Canada; Ottawa Institute of Systems Biology, Ottawa, ON, K1H 8M5, Canada
| | - Angela Cheung
- Gastroenterology and Hepatology, Department of Medicine, The Ottawa Hospital, Ottawa, ON, K1H 8M5, Canada; The Ottawa Hospital Research Institute, Chronic Disease Program, Ottawa, ON, K1Y 4E9, Canada
| | - Michael Downey
- Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON, K1H 8M5, Canada; Ottawa Institute of Systems Biology, Ottawa, ON, K1H 8M5, Canada
| | - Erin E Mulvihill
- University of Ottawa Heart Institute, Ottawa, ON, K1Y 4W7, Canada; Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, K1H 8M5, Canada
| | - Kyoung-Han Kim
- University of Ottawa Heart Institute, Ottawa, ON, K1Y 4W7, Canada; Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON, K1H 8M5, Canada.
| |
Collapse
|
|
14
|
Luukkonen PK, Qadri S, Ahlholm N, Porthan K, Männistö V, Sammalkorpi H, Penttilä AK, Hakkarainen A, Lehtimäki TE, Gaggini M, Gastaldelli A, Ala-Korpela M, Orho-Melander M, Arola J, Juuti A, Pihlajamäki J, Hodson L, Yki-Järvinen H. Distinct contributions of metabolic dysfunction and genetic risk factors in the pathogenesis of non-alcoholic fatty liver disease. J Hepatol 2022; 76:526-535. [PMID: 34710482 PMCID: PMC8852745 DOI: 10.1016/j.jhep.2021.10.013] [Citation(s) in RCA: 109] [Impact Index Per Article: 36.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 10/09/2021] [Accepted: 10/14/2021] [Indexed: 12/14/2022]
Abstract
BACKGROUND & AIMS There is substantial inter-individual variability in the risk of non-alcoholic fatty liver disease (NAFLD). Part of which is explained by insulin resistance (IR) ('MetComp') and part by common modifiers of genetic risk ('GenComp'). We examined how IR on the one hand and genetic risk on the other contribute to the pathogenesis of NAFLD. METHODS We studied 846 individuals: 492 were obese patients with liver histology and 354 were individuals who underwent intrahepatic triglyceride measurement by proton magnetic resonance spectroscopy. A genetic risk score was calculated using the number of risk alleles in PNPLA3, TM6SF2, MBOAT7, HSD17B13 and MARC1. Substrate concentrations were assessed by serum NMR metabolomics. In subsets of participants, non-esterified fatty acids (NEFAs) and their flux were assessed by D5-glycerol and hyperinsulinemic-euglycemic clamp (n = 41), and hepatic de novo lipogenesis (DNL) was measured by D2O (n = 61). RESULTS We found that substrate surplus (increased concentrations of 28 serum metabolites including glucose, glycolytic intermediates, and amino acids; increased NEFAs and their flux; increased DNL) characterized the 'MetComp'. In contrast, the 'GenComp' was not accompanied by any substrate excess but was characterized by an increased hepatic mitochondrial redox state, as determined by serum β-hydroxybutyrate/acetoacetate ratio, and inhibition of hepatic pathways dependent on tricarboxylic acid cycle activity, such as DNL. Serum β-hydroxybutyrate/acetoacetate ratio correlated strongly with all histological features of NAFLD. IR and hepatic mitochondrial redox state conferred additive increases in histological features of NAFLD. CONCLUSIONS These data show that the mechanisms underlying 'Metabolic' and 'Genetic' components of NAFLD are fundamentally different. These findings may have implications with respect to the diagnosis and treatment of NAFLD. LAY SUMMARY The pathogenesis of non-alcoholic fatty liver disease can be explained in part by a metabolic component, including obesity, and in part by a genetic component. Herein, we demonstrate that the mechanisms underlying these components are fundamentally different: the metabolic component is characterized by hepatic oversupply of substrates, such as sugars, lipids and amino acids. In contrast, the genetic component is characterized by impaired hepatic mitochondrial function, making the liver less able to metabolize these substrates.
Collapse
Affiliation(s)
- Panu K Luukkonen
- Department of Internal Medicine, Yale University, New Haven, CT, USA; Department of Medicine, University of Helsinki and Helsinki University Hospital, Finland; Minerva Foundation Institute for Medical Research, Helsinki, Finland.
| | - Sami Qadri
- Department of Medicine, University of Helsinki and Helsinki University Hospital, Finland; Minerva Foundation Institute for Medical Research, Helsinki, Finland
| | - Noora Ahlholm
- Department of Medicine, University of Helsinki and Helsinki University Hospital, Finland; Minerva Foundation Institute for Medical Research, Helsinki, Finland
| | - Kimmo Porthan
- Department of Medicine, University of Helsinki and Helsinki University Hospital, Finland; Minerva Foundation Institute for Medical Research, Helsinki, Finland
| | - Ville Männistö
- Department of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland
| | - Henna Sammalkorpi
- Department of Abdominal Surgery, Abdominal Center, University of Helsinki and Helsinki University Hospital, Finland
| | - Anne K Penttilä
- Department of Abdominal Surgery, Abdominal Center, University of Helsinki and Helsinki University Hospital, Finland
| | - Antti Hakkarainen
- Department of Radiology, HUS Medical Imaging Center, University of Helsinki and Helsinki University Hospital, Finland; Department of Neuroscience and Biomedical Engineering, Aalto University School of Science, Espoo, Finland
| | - Tiina E Lehtimäki
- Department of Radiology, HUS Medical Imaging Center, University of Helsinki and Helsinki University Hospital, Finland
| | | | | | - Mika Ala-Korpela
- Computational Medicine, Faculty of Medicine, University of Oulu and Biocenter Oulu, Finland; Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland; University of Eastern Finland, Kuopio, Finland; NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland
| | - Marju Orho-Melander
- Department of Clinical Sciences, Diabetes and Endocrinology, University Hospital Malmö, Lund University, Malmö, Sweden
| | - Johanna Arola
- Department of Pathology, University of Helsinki and Helsinki University Hospital, Finland
| | - Anne Juuti
- Department of Abdominal Surgery, Abdominal Center, University of Helsinki and Helsinki University Hospital, Finland
| | - Jussi Pihlajamäki
- Institute of Public Health and Clinical Nutrition, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland; Department of Medicine, Endocrinology and Clinical Nutrition, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland
| | - Leanne Hodson
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford & NIHR Oxford Biomedical Research Centre, Oxford University Hospitals Foundation Trust, UK
| | - Hannele Yki-Järvinen
- Department of Medicine, University of Helsinki and Helsinki University Hospital, Finland; Minerva Foundation Institute for Medical Research, Helsinki, Finland.
| |
Collapse
|
|
15
|
Guerra S, Mocciaro G, Gastaldelli A. Adipose tissue insulin resistance and lipidome alterations as the characterizing factors of non-alcoholic steatohepatitis. Eur J Clin Invest 2022; 52:e13695. [PMID: 34695228 DOI: 10.1111/eci.13695] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 09/16/2021] [Accepted: 10/15/2021] [Indexed: 12/13/2022]
Abstract
BACKGROUND The prevalence of non-alcoholic fatty liver disease (NAFLD) is now 25% in the general population but increases to more than 55% in subjects with obesity and/or type 2 diabetes. Simple steatosis (NAFL) can develop into more severe forms, that is non-alcoholic steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma leading to death. METHODS In this narrative review, we have discussed the current knowledge in the pathophysiology of fatty liver disease, including both metabolic and non-metabolic factors, insulin resistance, mitochondrial function, as well as the markers of liver damage, giving attention to the alterations in lipid metabolism and production of lipotoxic lipids. RESULTS Insulin resistance, particularly in the adipose tissue, is the main driver of NAFLD due to the excess release of fatty acids. Lipidome analyses have shown that several lipids, including DAGs and ceramides, and especially if they contain saturated lipids, act as bioactive compounds, toxic to the cells. Lipids can also affect mitochondrial function. Not only lipids, but also amino acid metabolism is impaired in NAFL/NASH, and some amino acids, as branched-chain and aromatic amino acids, glutamate, serine and glycine, have been linked to impaired metabolism, insulin resistance and severity of NAFLD and serine is a precursor of ceramides. CONCLUSIONS The measurement of lipotoxic species and adipose tissue dysfunction can help to identify individuals at risk of progression to NASH.
Collapse
Affiliation(s)
- Sara Guerra
- Institute of Clinical Physiology (IFC), National Research Council (CNR), Pisa, Italy.,Sant'Anna School of Advanced Studies, Pisa, Italy
| | - Gabriele Mocciaro
- Institute of Clinical Physiology (IFC), National Research Council (CNR), Pisa, Italy
| | - Amalia Gastaldelli
- Institute of Clinical Physiology (IFC), National Research Council (CNR), Pisa, Italy.,Sant'Anna School of Advanced Studies, Pisa, Italy
| |
Collapse
|
|
16
|
Pindozzi F, Socci C, Bissolati M, Marchi M, Devecchi E, Saibene A, Conte C. Role of nutritional ketosis in the improvement of metabolic parameters following bariatric surgery. World J Diabetes 2022; 13:54-64. [PMID: 35070059 PMCID: PMC8771267 DOI: 10.4239/wjd.v13.i1.54] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2021] [Revised: 06/29/2021] [Accepted: 01/05/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Ketone bodies (KB) might act as potential metabolic modulators besides serving as energy substrates. Bariatric metabolic surgery (BMS) offers a unique opportunity to study nutritional ketosis, as acute postoperative caloric restriction leads to increased lipolysis and circulating free fatty acids.
AIM To characterize the relationship between KB production, weight loss (WL) and metabolic changes following BMS.
METHODS For this retrospective study we enrolled male and female subjects aged 18-65 years who underwent BMS at a single Institution. Data on demographics, anthropometrics, body composition, laboratory values and urinary KB were collected.
RESULTS Thirty-nine patients had data available for analyses [74.4% women, mean age 46.5 ± 9.0 years, median body mass index 41.0 (38.5; 45.4) kg/m2, fat mass 45.2% ± 6.2%, 23.1% had diabetes, 43.6% arterial hypertension and 74.4% liver steatosis]. At 46.0 ± 13.6 d post-surgery, subjects had lost 12.0% ± 3.6% of pre-operative weight. Sixty-nine percent developed ketonuria. Those with nutritional ketosis were significantly younger [42.9 (37.6; 50.7) years vs 51.9 (48.3; 59.9) years, P = 0.018], and had significantly lower fasting glucose [89.5 (82.5; 96.3) mg/dL vs 96.0 (91.0; 105.3) mg/dL, P = 0.025] and triglyceride levels [108.0 (84.5; 152.5) mg/dL vs 152.0 (124.0; 186.0) mg/dL, P = 0.045] vs those with ketosis. At 6 mo, percent WL was greater in those with postoperative ketosis (-27.5% ± 5.1% vs 23.8% ± 4.3%, P = 0.035). Urinary KBs correlated with percent WL at 6 and 12 mo. Other metabolic changes were similar.
CONCLUSION Our data support the hypothesis that subjects with worse metabolic status have reduced ketogenic capacity and, thereby, exhibit a lower WL following BMS.
Collapse
Affiliation(s)
- Fioralba Pindozzi
- Unità di Chirurgia Generale Provinciale, Ospedale del Delta, Lagosanto (FE) 44023, Italy
| | - Carlo Socci
- Transplant and Metabolic/Bariatric Surgery Unit, IRCCS Ospedale San Raffaele, Milan 20132, Italy
| | - Massimiliano Bissolati
- Transplant and Metabolic/Bariatric Surgery Unit, IRCCS Ospedale San Raffaele, Milan 20132, Italy
| | - Monica Marchi
- Department of General Medicine, Diabetes and Endocrinology, IRCCS Ospedale San Raffaele, Milan 20132, Italy
| | - Elisabetta Devecchi
- Department of General Medicine, Diabetes and Endocrinology, IRCCS Ospedale San Raffaele, Milan 20132, Italy
| | - Alessandro Saibene
- Department of General Medicine, Diabetes and Endocrinology, IRCCS Ospedale San Raffaele, Milan 20132, Italy
| | - Caterina Conte
- Department of Human Sciences and Promotion of the Quality of Life, San Raffaele Open University, Rome 00166, Italy
- Department of Endocrinology, Nutrition and Metabolic Diseases, IRCCS MultiMedica, Milan 20099, Italy
| |
Collapse
|
|
17
|
Liu Z, Li Y, Liu Y, Yang D, Jiao Y, Liu Y. Expression and clinical significance of BDH1 in liver cancer. Medicine (Baltimore) 2021; 100:e28013. [PMID: 35049211 PMCID: PMC9191611 DOI: 10.1097/md.0000000000028013] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Accepted: 11/11/2021] [Indexed: 12/16/2022] Open
Abstract
Liver cancer is a deadly disease with generally poor patient outcomes. BDH1 is a key enzyme that regulates the metabolism and synthesis of ketone bodies. This study sought to explore the prognostic relevance of BDH1 mRNA expression in liver cancer.We utilized the Cancer Genome Atlas datasets to analyze the relationship between BDH1 expression and clinical outcomes. We used Kaplan-Meier curves and Cox analyses to explore the relevance of BDH1 mRNA levels to patient prognosis. Further gene set enrichment analysis was conducted as a means of comparing differences in gene expression as a function of BDH1 expression.Liver cancer samples exhibited significantly decreased BDH1 mRNA expression, and that this downregulation was correlated with a number of clinicopathological variables including gender, histologic grade, stage, TNM classification, and both overall and relapse-free survival. We further determined that BDH1 mRNA expression was an independent predictor of liver cancer patient prognosis. A subsequent gene set enrichment analysis found genes affected by BDH1 expression to be those enriched in pathways relating to MYC and wnt/β-catenin signaling.Our preliminary findings demonstrate for the first time that low expression of BDH1 mRNA is a potentially valuable independent prognostic indicator for liver cancer detection.
Collapse
Affiliation(s)
- Zhicheng Liu
- Department of Gastrointestinal Surgery, the First Hospital of Jilin University, Changchun, Jilin, China
| | - Yanqing Li
- Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, Jilin, China
- Department of Thyroid and Neck, the Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Ying Liu
- Department of General Surgery, the Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, Jilin, China
| | - Dingquan Yang
- Department of General Surgery, the Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, Jilin, China
| | - Yan Jiao
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Yunpeng Liu
- Department of Thoracic Surgery, the First Hospital of Jilin University, Changchun, Jilin, China
| |
Collapse
|
|
18
|
Ghodsian N, Abner E, Emdin CA, Gobeil É, Taba N, Haas ME, Perrot N, Manikpurage HD, Gagnon É, Bourgault J, St-Amand A, Couture C, Mitchell PL, Bossé Y, Mathieu P, Vohl MC, Tchernof A, Thériault S, Khera AV, Esko T, Arsenault BJ. Electronic health record-based genome-wide meta-analysis provides insights on the genetic architecture of non-alcoholic fatty liver disease. Cell Rep Med 2021; 2:100437. [PMID: 34841290 PMCID: PMC8606899 DOI: 10.1016/j.xcrm.2021.100437] [Citation(s) in RCA: 86] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Revised: 10/07/2021] [Accepted: 10/12/2021] [Indexed: 12/12/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a complex disease linked to several chronic diseases. We aimed at identifying genetic variants associated with NAFLD and evaluating their functional consequences. We performed a genome-wide meta-analysis of 4 cohorts of electronic health record-documented NAFLD in participants of European ancestry (8,434 cases and 770,180 controls). We identify 5 potential susceptibility loci for NAFLD (located at or near GCKR, TR1B1, MAU2/TM6SF2, APOE, and PNPLA3). We also report a potentially causal effect of lower LPL expression in adipose tissue on NAFLD susceptibility and an effect of the FTO genotype on NAFLD. Positive genetic correlations between NAFLD and cardiometabolic diseases and risk factors such as body fat accumulation/distribution, lipoprotein-lipid levels, insulin resistance, and coronary artery disease and negative genetic correlations with parental lifespan, socio-economic status, and acetoacetate levels are observed. This large GWAS meta-analysis reveals insights into the genetic architecture of NAFLD.
Collapse
Affiliation(s)
- Nooshin Ghodsian
- Centre de Recherche de l’Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec, QC, Canada
| | - Erik Abner
- Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Riia 23b, 51010, Estonia
| | - Connor A. Emdin
- Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA 02114, USA
| | - Émilie Gobeil
- Centre de Recherche de l’Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec, QC, Canada
| | - Nele Taba
- Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Riia 23b, 51010, Estonia
- Institute of Molecular and Cell Biology, University of Tartu, Tartu, Riia 23, 51010, Estonia
| | - Mary E. Haas
- Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA
- Department of Molecular Biology, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Nicolas Perrot
- Centre de Recherche de l’Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec, QC, Canada
| | - Hasanga D. Manikpurage
- Centre de Recherche de l’Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec, QC, Canada
| | - Éloi Gagnon
- Centre de Recherche de l’Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec, QC, Canada
| | - Jérôme Bourgault
- Centre de Recherche de l’Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec, QC, Canada
| | - Alexis St-Amand
- Centre de Recherche de l’Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec, QC, Canada
| | - Christian Couture
- Centre de Recherche de l’Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec, QC, Canada
| | - Patricia L. Mitchell
- Centre de Recherche de l’Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec, QC, Canada
| | - Yohan Bossé
- Centre de Recherche de l’Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec, QC, Canada
- Department of Molecular Medicine, Faculty of Medicine, Université Laval, Québec, QC, Canada
| | - Patrick Mathieu
- Centre de Recherche de l’Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec, QC, Canada
- Department of Surgery, Faculty of Medicine, Université Laval, Québec, QC, Canada
| | - Marie-Claude Vohl
- Centre NUTRISS, Institut sur la Nutrition et les Aliments Fonctionnels, Université Laval, Québec, QC, Canada
- School of Nutrition, Université Laval, Québec, QC, Canada
| | - André Tchernof
- Centre de Recherche de l’Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec, QC, Canada
- School of Nutrition, Université Laval, Québec, QC, Canada
| | - Sébastien Thériault
- Centre de Recherche de l’Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec, QC, Canada
- Department of Molecular Biology, Medical Biochemistry and Pathology, Faculty of Medicine, Université Laval, Québec, QC, Canada
| | - Amit V. Khera
- Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA 02114, USA
- Center for Genomic Medicine, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Tõnu Esko
- Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Riia 23b, 51010, Estonia
| | - Benoit J. Arsenault
- Centre de Recherche de l’Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec, QC, Canada
- Department of Medicine, Faculty of Medicine, Université Laval, Québec, QC, Canada
| |
Collapse
|
|
19
|
Robinson EJ, Taddeo MC, Chu X, Shi W, Wood C, Still C, Rovnyak VG, Rovnyak D. Aqueous Metabolite Trends for the Progression of Nonalcoholic Fatty Liver Disease in Female Bariatric Surgery Patients by Targeted 1H-NMR Metabolomics. Metabolites 2021; 11:metabo11110737. [PMID: 34822395 PMCID: PMC8619318 DOI: 10.3390/metabo11110737] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2021] [Revised: 10/20/2021] [Accepted: 10/21/2021] [Indexed: 01/14/2023] Open
Abstract
Determining biomarkers and better characterizing the biochemical progression of nonalcoholic fatty liver disease (NAFLD) remains a clinical challenge. A targeted 1H-NMR study of serum, combined with clinical variables, detected and localized biomarkers to stages of NAFLD in morbidly obese females. Pre-surgery serum samples from 100 middle-aged, morbidly obese female subjects, grouped on gold-standard liver wedge biopsies (non-NAFLD; steatosis; and fibrosis) were collected, extracted, and analyzed in aqueous (D2O) buffer (1H, 600 MHz). Profiled concentrations were subjected to exploratory statistical analysis. Metabolites varying significantly between the non-NAFLD and steatosis groups included the ketone bodies 3-hydroxybutyrate (↓; p = 0.035) and acetone (↓; p = 0.012), and also alanine (↑; p = 0.004) and a putative pyruvate signal (↑; p = 0.003). In contrast, the steatosis and fibrosis groups were characterized by 2-hydroxyisovalerate (↑; p = 0.023), betaine (↓; p = 0.008), hypoxanthine (↓; p = 0.003), taurine (↓; p = 0.001), 2-hydroxybutyrate (↑; p = 0.045), 3-hydroxyisobutyrate (↑; p = 0.046), and increasing medium chain fatty acids. Exploratory classification models with and without clinical variables exhibited overall success rates ca. 75–85%. In the study conditions, inhibition of fatty acid oxidation and disruption of the hepatic urea cycle are supported as early features of NAFLD that continue in fibrosis. In fibrosis, markers support inflammation, hepatocyte damage, and decreased liver function. Complementarity of NMR concentrations and clinical information in classification models is shown. A broader hypothesis that standard-of-care sera can yield metabolomic information is supported.
Collapse
Affiliation(s)
- Emma J. Robinson
- Department of Chemistry, Bucknell University, 1 Dent Drive, Lewisburg, PA 17837, USA; (E.J.R.); (M.C.T.)
| | - Matthew C. Taddeo
- Department of Chemistry, Bucknell University, 1 Dent Drive, Lewisburg, PA 17837, USA; (E.J.R.); (M.C.T.)
| | - Xin Chu
- The Obesity Institute, Geisinger, Danville, PA 17822, USA; (X.C.); (W.S.); (C.W.); (C.S.)
| | - Weixing Shi
- The Obesity Institute, Geisinger, Danville, PA 17822, USA; (X.C.); (W.S.); (C.W.); (C.S.)
| | - Craig Wood
- The Obesity Institute, Geisinger, Danville, PA 17822, USA; (X.C.); (W.S.); (C.W.); (C.S.)
| | - Christopher Still
- The Obesity Institute, Geisinger, Danville, PA 17822, USA; (X.C.); (W.S.); (C.W.); (C.S.)
| | | | - David Rovnyak
- Department of Chemistry, Bucknell University, 1 Dent Drive, Lewisburg, PA 17837, USA; (E.J.R.); (M.C.T.)
- Correspondence:
| |
Collapse
|
|
20
|
Goon DE, Ab-Rahim S, Mohd Sakri AH, Mazlan M, Tan JK, Abdul Aziz M, Mohd Noor N, Ibrahim E, Sheikh Abdul Kadir SH. Untargeted serum metabolites profiling in high-fat diet mice supplemented with enhanced palm tocotrienol-rich fraction using UHPLC-MS. Sci Rep 2021; 11:21001. [PMID: 34697380 PMCID: PMC8546078 DOI: 10.1038/s41598-021-00454-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Accepted: 10/01/2021] [Indexed: 01/14/2023] Open
Abstract
Excessive high fat dietary intake promotes risk of developing non-alcoholic fatty liver disease (NAFLD) and predisposed with oxidative stress. Palm based tocotrienol-rich fraction (TRF) has been reported able to ameliorate oxidative stress but exhibited poor bioavailability. Thus, we investigated whether an enhanced formulation of TRF in combination with palm kernel oil (medium-chain triglycerides) (ETRF) could ameliorate the effect of high-fat diet (HFD) on leptin-deficient male mice. All the animals were divided into HFD only (HFD group), HFD supplemented with ETRF (ETRF group) and HFD supplemented with TRF (TRF group) and HFD supplemented with PKO (PKO group). After 6 weeks, sera were collected for untargeted metabolite profiling using UHPLC-Orbitrap MS. Univariate analysis unveiled alternation in metabolites for bile acids, amino acids, fatty acids, sphingolipids, and alkaloids. Bile acids, lysine, arachidonic acid, and sphingolipids were downregulated while xanthine and hypoxanthine were upregulated in TRF and ETRF group. The regulation of these metabolites suggests that ETRF may promote better fatty acid oxidation, reduce oxidative stress and pro-inflammatory metabolites and acts as anti-inflammatory in fatty liver compared to TRF. Metabolites regulated by ETRF also provide insight of its role in fatty liver. However, further investigation is warranted to identify the mechanisms involved.
Collapse
Affiliation(s)
- Danial Efendy Goon
- Institute of Medical Molecular Biotechnology (IMMB), Faculty of Medicine, Universiti Teknologi MARA (UiTM), Cawangan Selangor, Sungai Buloh, Selangor, Malaysia
- Institute of Pathology, Laboratory and Forensic Medicine (I-PPerForM), Faculty of Medicine, Universiti Teknologi MARA (UiTM), Cawangan Selangor, Sungai Buloh, Selangor, Malaysia
- Department of Biochemistry, Faculty of Medicine, Universiti Teknologi MARA (UiTM), Cawangan Selangor, Sungai Buloh, Selangor, Malaysia
| | - Sharaniza Ab-Rahim
- Department of Biochemistry, Faculty of Medicine, Universiti Teknologi MARA (UiTM), Cawangan Selangor, Sungai Buloh, Selangor, Malaysia.
| | - Amir Hakimi Mohd Sakri
- Institute of Medical Molecular Biotechnology (IMMB), Faculty of Medicine, Universiti Teknologi MARA (UiTM), Cawangan Selangor, Sungai Buloh, Selangor, Malaysia
- Department of Physiology, Faculty of Medicine, Universiti Teknologi MARA (UiTM), Cawangan Selangor, Sungai Buloh, Selangor, Malaysia
| | - Musalmah Mazlan
- Department of Biochemistry, Faculty of Medicine, Universiti Teknologi MARA (UiTM), Cawangan Selangor, Sungai Buloh, Selangor, Malaysia
| | - Jen Kit Tan
- Department of Biochemistry, Faculty of Medicine, Universiti Kebangsaan Malaysia, 56000, Kuala Lumpur, Malaysia
| | - Mardiana Abdul Aziz
- Department of Pathology, Faculty of Medicine, Universiti Teknologi MARA (UiTM), Cawangan Selangor, 47000, Sungai Buloh, Selangor, Malaysia
| | - Norizal Mohd Noor
- Department of Pathology, Faculty of Medicine, Universiti Teknologi MARA (UiTM), Cawangan Selangor, 47000, Sungai Buloh, Selangor, Malaysia
| | - Effendi Ibrahim
- Department of Physiology, Faculty of Medicine, Universiti Teknologi MARA (UiTM), Cawangan Selangor, Sungai Buloh, Selangor, Malaysia
| | - Siti Hamimah Sheikh Abdul Kadir
- Institute of Pathology, Laboratory and Forensic Medicine (I-PPerForM), Faculty of Medicine, Universiti Teknologi MARA (UiTM), Cawangan Selangor, Sungai Buloh, Selangor, Malaysia.
- Department of Biochemistry, Faculty of Medicine, Universiti Teknologi MARA (UiTM), Cawangan Selangor, Sungai Buloh, Selangor, Malaysia.
| |
Collapse
|
|
21
|
Piras C, Noto A, Ibba L, Deidda M, Fanos V, Muntoni S, Leoni VP, Atzori L. Contribution of Metabolomics to the Understanding of NAFLD and NASH Syndromes: A Systematic Review. Metabolites 2021; 11:metabo11100694. [PMID: 34677409 PMCID: PMC8541039 DOI: 10.3390/metabo11100694] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 10/03/2021] [Accepted: 10/06/2021] [Indexed: 12/20/2022] Open
Abstract
Several differential panels of metabolites have been associated with the presence of metabolic syndrome and its related conditions, namely non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). This study aimed to perform a systematic review to summarize the most recent finding in terms of circulating biomarkers following NAFLD/NASH syndromes. Hence, the research was focused on NAFLD/NASH studies analysed by metabolomics approaches. Following Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines, a systematic search was conducted on the PubMed database. The inclusion criteria were (i) publication date between 2010 and 2021, (ii) presence of the combination of terms: metabolomics and NAFLD/NASH, and (iii) published in a scholarly peer-reviewed journal. Studies were excluded from the review if they were (i) single-case studies, (ii) unpublished thesis and dissertation studies, and (iii) not published in a peer-reviewed journal. Following these procedures, 10 eligible studies among 93 were taken into consideration. The metabolisms of amino acids, fatty acid, and vitamins were significantly different in patients affected by NAFLD and NASH compared to healthy controls. These findings suggest that low weight metabolites are an important indicator for NAFLD/NASH syndrome and there is a strong overlap between NAFLD/NASH and the metabolic syndrome. These findings may lead to new perspectives in early diagnosis, identification of novel biomarkers, and providing novel targets for pharmacological interventions.
Collapse
Affiliation(s)
- Cristina Piras
- Department of Biomedical Sciences, University of Cagliari, 09042 Monserrato, Italy; (C.P.); (L.I.); (S.M.); (V.P.L.); (L.A.)
| | - Antonio Noto
- Department of Biomedical Sciences, University of Cagliari, 09042 Monserrato, Italy; (C.P.); (L.I.); (S.M.); (V.P.L.); (L.A.)
- Correspondence:
| | - Luciano Ibba
- Department of Biomedical Sciences, University of Cagliari, 09042 Monserrato, Italy; (C.P.); (L.I.); (S.M.); (V.P.L.); (L.A.)
| | - Martino Deidda
- Department of Medical Sciences and Public Health, University of Cagliari, 09042 Monserrato, Italy;
| | - Vassilios Fanos
- Neonatal Intensive Care Unit, Department of Surgical Sciences, University of Cagliari, 09042 Monserrato, Italy;
| | - Sandro Muntoni
- Department of Biomedical Sciences, University of Cagliari, 09042 Monserrato, Italy; (C.P.); (L.I.); (S.M.); (V.P.L.); (L.A.)
| | - Vera Piera Leoni
- Department of Biomedical Sciences, University of Cagliari, 09042 Monserrato, Italy; (C.P.); (L.I.); (S.M.); (V.P.L.); (L.A.)
| | - Luigi Atzori
- Department of Biomedical Sciences, University of Cagliari, 09042 Monserrato, Italy; (C.P.); (L.I.); (S.M.); (V.P.L.); (L.A.)
| |
Collapse
|
|
22
|
Pan DZ, Miao Z, Comenho C, Rajkumar S, Koka A, Lee SHT, Alvarez M, Kaminska D, Ko A, Sinsheimer JS, Mohlke KL, Mancuso N, Muñoz-Hernandez LL, Herrera-Hernandez M, Tusié-Luna MT, Aguilar-Salinas C, Pietiläinen KH, Pihlajamäki J, Laakso M, Garske KM, Pajukanta P. Identification of TBX15 as an adipose master trans regulator of abdominal obesity genes. Genome Med 2021; 13:123. [PMID: 34340684 PMCID: PMC8327600 DOI: 10.1186/s13073-021-00939-2] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Accepted: 07/14/2021] [Indexed: 12/14/2022] Open
Abstract
Background Obesity predisposes individuals to multiple cardiometabolic disorders, including type 2 diabetes (T2D). As body mass index (BMI) cannot reliably differentiate fat from lean mass, the metabolically detrimental abdominal obesity has been estimated using waist-hip ratio (WHR). Waist-hip ratio adjusted for body mass index (WHRadjBMI) in turn is a well-established sex-specific marker for abdominal fat and adiposity, and a predictor of adverse metabolic outcomes, such as T2D. However, the underlying genes and regulatory mechanisms orchestrating the sex differences in obesity and body fat distribution in humans are not well understood. Methods We searched for genetic master regulators of WHRadjBMI by employing integrative genomics approaches on human subcutaneous adipose RNA sequencing (RNA-seq) data (n ~ 1400) and WHRadjBMI GWAS data (n ~ 700,000) from the WHRadjBMI GWAS cohorts and the UK Biobank (UKB), using co-expression network, transcriptome-wide association study (TWAS), and polygenic risk score (PRS) approaches. Finally, we functionally verified our genomic results using gene knockdown experiments in a human primary cell type that is critical for adipose tissue function. Results Here, we identified an adipose gene co-expression network that contains 35 obesity GWAS genes and explains a significant amount of polygenic risk for abdominal obesity and T2D in the UKB (n = 392,551) in a sex-dependent way. We showed that this network is preserved in the adipose tissue data from the Finnish Kuopio Obesity Study and Mexican Obesity Study. The network is controlled by a novel adipose master transcription factor (TF), TBX15, a WHRadjBMI GWAS gene that regulates the network in trans. Knockdown of TBX15 in human primary preadipocytes resulted in changes in expression of 130 network genes, including the key adipose TFs, PPARG and KLF15, which were significantly impacted (FDR < 0.05), thus functionally verifying the trans regulatory effect of TBX15 on the WHRadjBMI co-expression network. Conclusions Our study discovers a novel key function for the TBX15 TF in trans regulating an adipose co-expression network of 347 adipose, mitochondrial, and metabolically important genes, including PPARG, KLF15, PPARA, ADIPOQ, and 35 obesity GWAS genes. Thus, based on our converging genomic, transcriptional, and functional evidence, we interpret the role of TBX15 to be a main transcriptional regulator in the adipose tissue and discover its importance in human abdominal obesity. Supplementary Information The online version contains supplementary material available at 10.1186/s13073-021-00939-2.
Collapse
Affiliation(s)
- David Z Pan
- Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, USA.,Bioinformatics Interdepartmental Program, UCLA, Los Angeles, USA
| | - Zong Miao
- Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, USA.,Bioinformatics Interdepartmental Program, UCLA, Los Angeles, USA
| | - Caroline Comenho
- Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, USA
| | - Sandhya Rajkumar
- Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, USA.,Computational and Systems Biology Interdepartmental Program, UCLA, Los Angeles, USA
| | - Amogha Koka
- Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, USA
| | - Seung Hyuk T Lee
- Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, USA
| | - Marcus Alvarez
- Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, USA
| | - Dorota Kaminska
- Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, USA.,Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
| | - Arthur Ko
- Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, USA
| | - Janet S Sinsheimer
- Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, USA.,Department of Computational Medicine, David Geffen School of Medicine at UCLA, Los Angeles, USA
| | - Karen L Mohlke
- Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Nicholas Mancuso
- Center for Genetic Epidemiology, Department of Preventative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, USA
| | - Linda Liliana Muñoz-Hernandez
- Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Ave. Morones Prieto 3000, Monterrey, N.L., México, 64710.,Unidad de Investigación de Enfermedades Metabólicas, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.,Departamento de Endocrinología y Metabolismo del Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Miguel Herrera-Hernandez
- Departamento de Cirugía, Instituto Nacional de Ciencias Médicas y Nutrición, Mexico City, Mexico
| | - Maria Teresa Tusié-Luna
- Unidad de Biología Molecular y Medicina Genómica, Instituto de Investigaciones Biomédicas UNAM/ Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Carlos Aguilar-Salinas
- Unidad de Investigación de Enfermedades Metabólicas, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.,Departamento de Endocrinología y Metabolismo del Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Kirsi H Pietiläinen
- Obesity Research Unit, Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland.,Obesity Center, Endocrinology, Abdominal Center, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland
| | - Jussi Pihlajamäki
- Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland.,Department of Medicine, Endocrinology and Clinical Nutrition, Kuopio University Hospital, Kuopio, Finland
| | - Markku Laakso
- Department of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland
| | - Kristina M Garske
- Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, USA
| | - Päivi Pajukanta
- Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, USA. .,Bioinformatics Interdepartmental Program, UCLA, Los Angeles, USA. .,Institute for Precision Health at UCLA, Los Angeles, USA.
| |
Collapse
|
|
23
|
Guo F, Han M, Lin S, Ye H, Chen J, Zhu H, Lin W. Enteromorpha prolifera polysaccharide prevents high- fat diet-induced obesity in hamsters: A NMR-based metabolomic evaluation. J Food Sci 2021; 86:3672-3685. [PMID: 34191277 DOI: 10.1111/1750-3841.15818] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Revised: 04/26/2021] [Accepted: 05/28/2021] [Indexed: 12/31/2022]
Abstract
Enteromorpha prolifera polysaccharide (EP) has been shown to exhibit hypolipidemic and hypoglycemic activities in various experimental models. Here, an 1 H-NMR-based metabolomic study was conducted to explore the regulatory effects of EP on serum metabolic changes in obese hamsters. High-fat diet (HFD)-fed hamsters were orally administrated with EP (300, 450, or 600 mg/kg) once daily for 12 weeks. Compared with HFD-fed hamsters, EP treatment (450 and 600 mg/kg) significantly decreased the body weight (by 8.69 and 8.24%), liver weight (by 7.87 and 8.25%), epididymal white adipose tissue (by 19.54 and 17.26%), perirenal white adipose tissue (by 28.09 and 28.94%), serum total cholesterol (by 24.31 and 18.61%), triglyceride (by 30.64 and 31.38%), and low-density lipoprotein cholesterol (by 38.26 and 36.30%), respectively. In addition, EP intervention also significantly decreased hepatic cholesterol (by 23.20, 38.16, and 34.57%) and triglyceride content (by 17.78, 41.47, and 35.50%) as well as serum levels of alanine aminotransferase (ALT) and ALT/aspartate aminotransferase (AST) ratio. The serum samples of normal diet (ND) group, HFD group and HFD + EP 450 mg/kg (HFD + MEP) group were further analyzed by 1 H-NMR spectroscopy. Compared with ND group, 17 and 2 metabolites were significantly upregulated and downregulated in HFD group, respectively. Interestingly, EP treatment significantly downregulated nine metabolites and upregulated one metabolite when compared to those in HFD group. Our results indicated that EP intervention partially ameliorated HFD-induced metabolic dysfunction, and the most prominent metabolic pathways included citrate cycle, synthesis and degradation of ketone bodies, pyruvate metabolism, valine, leucine and isoleucine degradation, and arginine biosynthesis. PRACTICAL APPLICATION: Enteromorpha prolifera polysaccharide (EP), the main active component of Enteromorpha prolifera, is reported to have many biological activities. However, the antiobesity effect of EP and its corresponding metabolic mechanism have not been reported so far. The results of this study confirmed the antiobesity effect of EP on HFD-induced obese hamsters and elucidated its possible metabolic mechanism. Our study highlighted that EP might be used in weight-loss functional foods.
Collapse
Affiliation(s)
- Fuchuan Guo
- Department of Nutrition and Food Safety, School of Public Health, Fujian Medical University, FuZhou, P. R. China
| | - Mengyuan Han
- Department of Nutrition and Food Safety, School of Public Health, Fujian Medical University, FuZhou, P. R. China.,Department of Women's Health Care, Fujian Obstetrics and Gynecology Hospital, FuZhou, P. R. China
| | - Song Lin
- Department of Child Health Care, Fuqing Maternal and Child Health Care Hospital, FuQing, China
| | - Hui Ye
- Department of Nutrition and Food Safety, School of Public Health, Fujian Medical University, FuZhou, P. R. China
| | - Jiedong Chen
- Department of Nutrition and Food Safety, School of Public Health, Fujian Medical University, FuZhou, P. R. China
| | - Hongni Zhu
- Department of Nutrition and Food Safety, School of Public Health, Fujian Medical University, FuZhou, P. R. China
| | - Wenting Lin
- Department of Nutrition and Food Safety, School of Public Health, Fujian Medical University, FuZhou, P. R. China
| |
Collapse
|
|
24
|
Demyanova EV, Shcherbakova ES, Sall TS, Bakulin IG, Vakhitov TY, Sitkin SI. Non-targeted Serum Metabolomics Identifies Candidate Biomarkers Panels Associated with Nonalcoholic Fatty Liver Disease: A Pilot Study in Russian Male Patients. THE OPEN BIOMARKERS JOURNAL 2021; 11:17-27. [DOI: 10.2174/1875318302111010017] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Revised: 01/04/2021] [Accepted: 01/07/2021] [Indexed: 09/26/2023]
Abstract
Aims:
The aim of the present study was to explore changes in the serum metabolome of patients with NAFLD relative to healthy controls to identify biomarkers associated with steatosis or Non-Alcoholic Steatohepatitis (NASH).
Background:
The serum metabolome reflects changes at the organismal level. This is especially important in Non-Alcoholic Liver Disease (NAFLD), where changes in hormones, cytokines, enzymes and other metabolic alterations can affect the liver, as well as adipose tissue, skeletal muscle and other systems.
Objective:
The objectives were to conduct non-targeted serum metabolomics, data processing, and identification of candidate biomarkers, as well as panels and assessment of their prognostic value.
Materials and Methods:
Non-targeted metabolomic analysis of blood serum samples from 21 male patients with NAFLD (simple steatosis or NASH) and seven male Control group was performed using gas chromatography-mass spectrometry.
Results:
A total of 319 serum metabolites were detected in NAFLD and Control groups, several of which differed significantly between groups. The most discriminating biomarkers were 3-hydroxybutyric acid, 2-hydroxybutyric acid, 2,3-dihydroxybutyric acid, arabitol and 3-methyl-2-oxovaleric acid. Using a panel of three, four or more markers could distinguish patients with NAFLD from controls, and patients with NASH from those with simple steatosis.
Conclusion:
We identified candidate biomarkers for simple steatosis and NASH. Since NAFLD is a multifactorial disease, it is preferable to use a marker panel rather than individual metabolites. Markers may not only result from dysregulation of metabolic pathways in patients with NAFLD, they may also reflect adaptive responses to disease, including functional changes in the intestinal microbiota.
Collapse
|
|
25
|
Gong MJ, Zhu CY, Zou ZJ, Han B, Huang P. Therapeutic potential of puerarin against methionine-choline-deficient diet-induced non-alcoholic steatohepatitis determined by combination of 1H NMR spectroscopy-based metabonomics and 16S rRNA gene sequencing. J Pharm Biomed Anal 2021; 197:113964. [PMID: 33601157 DOI: 10.1016/j.jpba.2021.113964] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Revised: 02/05/2021] [Accepted: 02/06/2021] [Indexed: 12/12/2022]
Abstract
Previously published studies have revealed the protective effect of puerarin against non-alcoholic steatohepatitis (NASH), but the definite mechanism of this effect still remains unclear. The present work was an attempt to assess the beneficial effects and the underlying mechanisms of puerarin on methionine-choline-deficient (MCD) diet-induced NASH in C57BL/6 mice by using a combination of metabonomics and 16S rRNA gene sequencing technology. Nuclear magnetic resonance (NMR)-based metabonomics showed significant hepatic and urinary metabolic phenotype changes between MCD-diet fed mice and the healthy controls. A total of eight and thirteen metabolites were identified as differential metabolites associated with NASH in liver tissue and urine of mice, respectively. The proposed pathways mainly included pyrimidine metabolism, one-carbon metabolism, amino acid metabolism, glycolysis, tricarboxylic acid (TCA) cycle and synthesis and degradation of ketone bodies. Furthermore, 16S rRNA gene sequencing analysis delineated remarkable variations in gut microbiota profiles in response to MCD diet in mice and forty differential bacterial taxa related to NASH were found between the control and model group. Puerarin could improve hepatic steatosis and inflammation in NASH mice via partially ameliorating metabolic disorders and rebalancing the gut flora. Specifically, puerarin could inhibit lipopolysaccharide (LPS)-producing genus Helicobacter, and promote butyrate-producing genus Roseburia. These findings offered novel insights into the in-depth understanding of the pathogenesis of NASH and provided further evidence for the potential use of puerarin as an anti-NASH agent.
Collapse
Affiliation(s)
- Meng-Juan Gong
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, China; School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Cai-Yan Zhu
- The Sixth Affilicated Hospital, Sun Yat-sen University, Guangzhou 510655, China
| | - Zhong-Jie Zou
- School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Bin Han
- School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Ping Huang
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, China.
| |
Collapse
|
|
26
|
Common Transcriptional Program of Liver Fibrosis in Mouse Genetic Models and Humans. Int J Mol Sci 2021; 22:ijms22020832. [PMID: 33467660 PMCID: PMC7830925 DOI: 10.3390/ijms22020832] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Revised: 01/08/2021] [Accepted: 01/12/2021] [Indexed: 02/06/2023] Open
Abstract
Multifactorial metabolic diseases, such as non-alcoholic fatty liver disease, are a major burden to modern societies, and frequently present with no clearly defined molecular biomarkers. Herein we used system medicine approaches to decipher signatures of liver fibrosis in mouse models with malfunction in genes from unrelated biological pathways: cholesterol synthesis-Cyp51, notch signaling-Rbpj, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling-Ikbkg, and unknown lysosomal pathway-Glmp. Enrichment analyses of Kyoto Encyclopedia of Genes and Genomes (KEGG), Reactome and TRANScription FACtor (TRANSFAC) databases complemented with genome-scale metabolic modeling revealed fibrotic signatures highly similar to liver pathologies in humans. The diverse genetic models of liver fibrosis exposed a common transcriptional program with activated estrogen receptor alpha (ERα) signaling, and a network of interactions between regulators of lipid metabolism and transcription factors from cancer pathways and the immune system. The novel hallmarks of fibrosis are downregulated lipid pathways, including fatty acid, bile acid, and steroid hormone metabolism. Moreover, distinct metabolic subtypes of liver fibrosis were proposed, supported by unique enrichment of transcription factors based on the type of insult, disease stage, or potentially, also sex. The discovered novel features of multifactorial liver fibrotic pathologies could aid also in improved stratification of other fibrosis related pathologies.
Collapse
|
|
27
|
Asif S, Morrow NM, Mulvihill EE, Kim KH. Understanding Dietary Intervention-Mediated Epigenetic Modifications in Metabolic Diseases. Front Genet 2020; 11:590369. [PMID: 33193730 PMCID: PMC7593700 DOI: 10.3389/fgene.2020.590369] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2020] [Accepted: 09/21/2020] [Indexed: 12/12/2022] Open
Abstract
The global prevalence of metabolic disorders, such as obesity, diabetes and fatty liver disease, is dramatically increasing. Both genetic and environmental factors are well-known contributors to the development of these diseases and therefore, the study of epigenetics can provide additional mechanistic insight. Dietary interventions, including caloric restriction, intermittent fasting or time-restricted feeding, have shown promising improvements in patients' overall metabolic profiles (i.e., reduced body weight, improved glucose homeostasis), and an increasing number of studies have associated these beneficial effects with epigenetic alterations. In this article, we review epigenetic changes involved in both metabolic diseases and dietary interventions in primary metabolic tissues (i.e., adipose, liver, and pancreas) in hopes of elucidating potential biomarkers and therapeutic targets for disease prevention and treatment.
Collapse
Affiliation(s)
- Shaza Asif
- University of Ottawa Heart Institute, Ottawa, ON, Canada
- Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
| | - Nadya M. Morrow
- University of Ottawa Heart Institute, Ottawa, ON, Canada
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
| | - Erin E. Mulvihill
- University of Ottawa Heart Institute, Ottawa, ON, Canada
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
| | - Kyoung-Han Kim
- University of Ottawa Heart Institute, Ottawa, ON, Canada
- Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
| |
Collapse
|
|
28
|
Mey JT, Erickson ML, Axelrod CL, King WT, Flask CA, McCullough AJ, Kirwan JP. β-Hydroxybutyrate is reduced in humans with obesity-related NAFLD and displays a dose-dependent effect on skeletal muscle mitochondrial respiration in vitro. Am J Physiol Endocrinol Metab 2020; 319:E187-E195. [PMID: 32396388 PMCID: PMC7468782 DOI: 10.1152/ajpendo.00058.2020] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic fat accumulation and impaired insulin sensitivity. Reduced hepatic ketogenesis may promote these pathologies, but data are inconclusive in humans and the link between NAFLD and reduced insulin sensitivity remains obscure. We investigated individuals with obesity-related NAFLD and hypothesized that β-hydroxybutyrate (βOHB; the predominant ketone species) would be reduced and related to hepatic fat accumulation and insulin sensitivity. Furthermore, we hypothesized that ketones would impact skeletal muscle mitochondrial respiration in vitro. Hepatic fat was assessed by 1H-MRS in 22 participants in a parallel design, case control study [Control: n = 7, age 50 ± 6 yr, body mass index (BMI) 30 ± 1 kg/m2; NAFLD: n = 15, age 57 ± 3 yr, BMI 35 ± 1 kg/m2]. Plasma assessments were conducted in the fasted state. Whole body insulin sensitivity was determined by the gold-standard hyperinsulinemic-euglycemic clamp. The effect of ketone dose (0.5-5.0 mM) on mitochondrial respiration was conducted in human skeletal muscle cell culture. Fasting βOHB, a surrogate measure of hepatic ketogenesis, was reduced in NAFLD (-15.6%, P < 0.01) and correlated negatively with liver fat (r2 = 0.21, P = 0.03) and positively with insulin sensitivity (r2 = 0.30, P = 0.01). Skeletal muscle mitochondrial oxygen consumption increased with low-dose ketones, attributable to increases in basal respiration (135%, P < 0.05) and ATP-linked oxygen consumption (136%, P < 0.05). NAFLD pathophysiology includes impaired hepatic ketogenesis, which is associated with hepatic fat accumulation and impaired insulin sensitivity. This reduced capacity to produce ketones may be a potential link between NAFLD and NAFLD-associated reductions in whole body insulin sensitivity, whereby ketone concentrations impact skeletal muscle mitochondrial respiration.
Collapse
Affiliation(s)
- Jacob T Mey
- Integrated Physiology and Molecular Medicine, Pennington Biomedical Research Center, Baton Rouge, Louisiana
- Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio
| | - Melissa L Erickson
- Integrated Physiology and Molecular Medicine, Pennington Biomedical Research Center, Baton Rouge, Louisiana
- Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio
| | - Christopher L Axelrod
- Integrated Physiology and Molecular Medicine, Pennington Biomedical Research Center, Baton Rouge, Louisiana
- Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio
- Translational Services, Pennington Biomedical Research Center, Baton Rouge, Louisiana
| | - William T King
- Integrated Physiology and Molecular Medicine, Pennington Biomedical Research Center, Baton Rouge, Louisiana
| | - Chris A Flask
- Radiology and Biomedical Engineering, Case Western Reserve University School of Medicine, Cleveland, Ohio
| | | | - John P Kirwan
- Integrated Physiology and Molecular Medicine, Pennington Biomedical Research Center, Baton Rouge, Louisiana
- Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio
| |
Collapse
|
|
29
|
De Jesus DF, Orime K, Kaminska D, Kimura T, Basile G, Wang CH, Haertle L, Riemens R, Brown NK, Hu J, Männistö V, Silva AM, Dirice E, Tseng YH, Haaf T, Pihlajamäki J, Kulkarni RN. Parental metabolic syndrome epigenetically reprograms offspring hepatic lipid metabolism in mice. J Clin Invest 2020; 130:2391-2407. [PMID: 32250344 PMCID: PMC7190992 DOI: 10.1172/jci127502] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2019] [Accepted: 01/22/2020] [Indexed: 12/24/2022] Open
Abstract
The prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing worldwide. Although gene-environment interactions have been implicated in the etiology of several disorders, the impact of paternal and/or maternal metabolic syndrome on the clinical phenotypes of offspring and the underlying genetic and epigenetic contributors of NAFLD have not been fully explored. To this end, we used the liver-specific insulin receptor knockout (LIRKO) mouse, a unique nondietary model manifesting 3 hallmarks that confer high risk for the development of NAFLD: hyperglycemia, insulin resistance, and dyslipidemia. We report that parental metabolic syndrome epigenetically reprograms members of the TGF-β family, including neuronal regeneration-related protein (NREP) and growth differentiation factor 15 (GDF15). NREP and GDF15 modulate the expression of several genes involved in the regulation of hepatic lipid metabolism. In particular, NREP downregulation increases the protein abundance of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) and ATP-citrate lyase (ACLY) in a TGF-β receptor/PI3K/protein kinase B-dependent manner, to regulate hepatic acetyl-CoA and cholesterol synthesis. Reduced hepatic expression of NREP in patients with NAFLD and substantial correlations between low serum NREP levels and the presence of steatosis and nonalcoholic steatohepatitis highlight the clinical translational relevance of our findings in the context of recent preclinical trials implicating ACLY in NAFLD progression.
Collapse
Affiliation(s)
- Dario F. De Jesus
- Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, Massachusetts, USA
- Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, USA
- Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts, USA
- Graduate Program in Areas of Basic and Applied Biology (GABBA), Abel Salazar Biomedical Sciences Institute, University of Porto, Porto, Portugal
| | - Kazuki Orime
- Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, Massachusetts, USA
- Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, USA
- Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts, USA
| | - Dorota Kaminska
- Department of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
| | - Tomohiko Kimura
- Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, Massachusetts, USA
- Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, USA
- Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts, USA
| | - Giorgio Basile
- Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, Massachusetts, USA
- Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, USA
- Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts, USA
| | - Chih-Hao Wang
- Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Larissa Haertle
- Institute of Human Genetics, Julius Maximilians University, Würzburg, Würzburg, Germany
- Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany
| | - Renzo Riemens
- Institute of Human Genetics, Julius Maximilians University, Würzburg, Würzburg, Germany
| | - Natalie K. Brown
- Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, Massachusetts, USA
- Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, USA
- Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts, USA
| | - Jiang Hu
- Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, Massachusetts, USA
- Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, USA
- Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts, USA
| | - Ville Männistö
- Department of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland
| | - Amélia M. Silva
- Department of Biology and Environment, School of Life and Environmental Sciences, and
- Centre for the Research and Technology of Agro-Environmental and Biological Sciences, University of Trás-os-Montes and Alto Douro, Vila Real, Portugal
| | - Ercument Dirice
- Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, Massachusetts, USA
- Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, USA
- Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts, USA
| | - Yu-Hua Tseng
- Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Thomas Haaf
- Institute of Human Genetics, Julius Maximilians University, Würzburg, Würzburg, Germany
| | - Jussi Pihlajamäki
- Department of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
- Clinical Nutrition and Obesity Center, Kuopio University Hospital, Kuopio, Finland
| | - Rohit N. Kulkarni
- Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, Massachusetts, USA
- Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, USA
- Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts, USA
| |
Collapse
|
|
30
|
Silva RA, Pereira TC, Souza AR, Ribeiro PR. 1H NMR-based metabolite profiling for biomarker identification. Clin Chim Acta 2020; 502:269-279. [PMID: 31778675 DOI: 10.1016/j.cca.2019.11.015] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Revised: 11/11/2019] [Accepted: 11/12/2019] [Indexed: 12/11/2022]
|
|
31
|
Staňková P, Kučera O, Peterová E, Lotková H, Maseko TE, Nožičková K, Červinková Z. Adaptation of Mitochondrial Substrate Flux in a Mouse Model of Nonalcoholic Fatty Liver Disease. Int J Mol Sci 2020; 21:1101. [PMID: 32046101 PMCID: PMC7036817 DOI: 10.3390/ijms21031101] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Revised: 02/02/2020] [Accepted: 02/05/2020] [Indexed: 12/30/2022] Open
Abstract
Maladaptation of mitochondrial oxidative flux seems to be a considerable feature of nonalcoholic fatty liver disease (NAFLD). The aim of this work was to induce NAFLD in mice fed a Western-style diet (WD) and to evaluate liver mitochondrial functions. Experiments were performed on male C57BL/6J mice fed with a control diet or a WD for 24 weeks. Histological changes in liver and adipose tissue as well as hepatic expression of fibrotic and inflammatory genes and proteins were evaluated. The mitochondrial respiration was assessed by high-resolution respirometry. Oxidative stress was evaluated by measuring lipoperoxidation, glutathione, and reactive oxygen species level. Feeding mice a WD induced adipose tissue inflammation and massive liver steatosis accompanied by mild inflammation and fibrosis. We found decreased succinate-activated mitochondrial respiration and decreased succinate dehydrogenase (SDH) activity in the mice fed a WD. The oxidative flux with other substrates was not affected. We observed increased ketogenic capacity, but no impact on the capacity for fatty acid oxidation. We did not confirm the presence of oxidative stress. Mitochondria in this stage of the disease are adapted to increased substrate flux. However, inhibition of SDH can lead to the accumulation of succinate, an important signaling molecule associated with inflammation, fibrosis, and carcinogenesis.
Collapse
Affiliation(s)
- Pavla Staňková
- Department of Physiology, Faculty of Medicine in Hradec Králové, Charles University, Šimkova 870, 500 03 Hradec Králové, Czech Republic; (P.S.); (H.L.); (T.E.M.); (K.N.); (Z.Č.)
| | - Otto Kučera
- Department of Physiology, Faculty of Medicine in Hradec Králové, Charles University, Šimkova 870, 500 03 Hradec Králové, Czech Republic; (P.S.); (H.L.); (T.E.M.); (K.N.); (Z.Č.)
| | - Eva Peterová
- Department of Medical Biochemistry, Faculty of Medicine in Hradec Králové, Charles University, Šimkova 870, 500 03 Hradec Králové, Czech Republic;
| | - Halka Lotková
- Department of Physiology, Faculty of Medicine in Hradec Králové, Charles University, Šimkova 870, 500 03 Hradec Králové, Czech Republic; (P.S.); (H.L.); (T.E.M.); (K.N.); (Z.Č.)
| | - Tumisang Edward Maseko
- Department of Physiology, Faculty of Medicine in Hradec Králové, Charles University, Šimkova 870, 500 03 Hradec Králové, Czech Republic; (P.S.); (H.L.); (T.E.M.); (K.N.); (Z.Č.)
| | - Kateřina Nožičková
- Department of Physiology, Faculty of Medicine in Hradec Králové, Charles University, Šimkova 870, 500 03 Hradec Králové, Czech Republic; (P.S.); (H.L.); (T.E.M.); (K.N.); (Z.Č.)
| | - Zuzana Červinková
- Department of Physiology, Faculty of Medicine in Hradec Králové, Charles University, Šimkova 870, 500 03 Hradec Králové, Czech Republic; (P.S.); (H.L.); (T.E.M.); (K.N.); (Z.Č.)
| |
Collapse
|
|
32
|
Hepatic FATP5 expression is associated with histological progression and loss of hepatic fat in NAFLD patients. J Gastroenterol 2020; 55:227-243. [PMID: 31602526 DOI: 10.1007/s00535-019-01633-2] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2019] [Accepted: 09/19/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are characterized by the accumulation of excess hepatic fat. However, in the progression from NASH to cirrhosis, hepatic fat is often lost. Our aim was to elucidate the mechanism underlying hepatic fat loss during NASH progression. METHODS Liver biopsies were performed at The University of Tokyo Hospital between November 2011 and March 2016 on 146 patients with NAFLD and 14 patients with cryptogenic cirrhosis who were not being treated with any diabetes or dyslipidemia drugs. Among them, 70 patients underwent liver biopsy after an overnight fast, and 90 patients were biopsied 5 h after an oral glucose tolerance test. Expression differences in genes encoding several fatty acid metabolism-related factors were examined and correlated with hepatic histological changes based on NAFLD activity scores. Prospective patient follow-up continued until June 2018. RESULTS The level of fatty acid transport protein 5 (FATP5), which is associated with free fatty acid intake, was significantly and inversely correlated with features of histological progression, including ballooning and fibrosis. This was confirmed by immunohistochemical analysis. Transcript levels of genes encoding fatty acid metabolism-related proteins were comparable between NASH with severe fibrosis and cryptogenic cirrhosis. Furthermore, a prospective cohort study demonstrated that low FATP5 expression was the most significant risk factor for hepatic fat loss. CONCLUSIONS Decreased hepatic FATP5 expression in NAFLD is linked to histological progression, and may be associated with hepatic fat loss during NASH progression to cirrhosis.
Collapse
|
|
33
|
Beyoğlu D, Idle JR. Metabolomic and Lipidomic Biomarkers for Premalignant Liver Disease Diagnosis and Therapy. Metabolites 2020; 10:E50. [PMID: 32012846 PMCID: PMC7074571 DOI: 10.3390/metabo10020050] [Citation(s) in RCA: 60] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Revised: 01/24/2020] [Accepted: 01/26/2020] [Indexed: 02/07/2023] Open
Abstract
In recent years, there has been a plethora of attempts to discover biomarkers that are more reliable than α-fetoprotein for the early prediction and prognosis of hepatocellular carcinoma (HCC). Efforts have involved such fields as genomics, transcriptomics, epigenetics, microRNA, exosomes, proteomics, glycoproteomics, and metabolomics. HCC arises against a background of inflammation, steatosis, and cirrhosis, due mainly to hepatic insults caused by alcohol abuse, hepatitis B and C virus infection, adiposity, and diabetes. Metabolomics offers an opportunity, without recourse to liver biopsy, to discover biomarkers for premalignant liver disease, thereby alerting the potential of impending HCC. We have reviewed metabolomic studies in alcoholic liver disease (ALD), cholestasis, fibrosis, cirrhosis, nonalcoholic fatty liver (NAFL), and nonalcoholic steatohepatitis (NASH). Specificity was our major criterion in proposing clinical evaluation of indole-3-lactic acid, phenyllactic acid, N-lauroylglycine, decatrienoate, N-acetyltaurine for ALD, urinary sulfated bile acids for cholestasis, cervonoyl ethanolamide for fibrosis, 16α-hydroxyestrone for cirrhosis, and the pattern of acyl carnitines for NAFL and NASH. These examples derive from a large body of published metabolomic observations in various liver diseases in adults, adolescents, and children, together with animal models. Many other options have been tabulated. Metabolomic biomarkers for premalignant liver disease may help reduce the incidence of HCC.
Collapse
Affiliation(s)
| | - Jeffrey R. Idle
- Arthur G. Zupko’s Division of Systems Pharmacology and Pharmacogenomics, Arnold & Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, 75 Dekalb Avenue, Brooklyn, NY 11201, USA;
| |
Collapse
|
|
34
|
High Protein Diet and Metabolic Plasticity in Non-Alcoholic Fatty Liver Disease: Myths and Truths. Nutrients 2019; 11:nu11122985. [PMID: 31817648 PMCID: PMC6950466 DOI: 10.3390/nu11122985] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Revised: 11/27/2019] [Accepted: 11/30/2019] [Indexed: 02/07/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is characterized by lipid accumulation within the liver affecting 1 in 4 people worldwide. As the new silent killer of the twenty-first century, NAFLD impacts on both the request and the availability of new liver donors. The liver is the first line of defense against endogenous and exogenous metabolites and toxins. It also retains the ability to switch between different metabolic pathways according to food type and availability. This ability becomes a disadvantage in obesogenic societies where most people choose a diet based on fats and carbohydrates while ignoring vitamins and fiber. The chronic exposure to fats and carbohydrates induces dramatic changes in the liver zonation and triggers the development of insulin resistance. Common believes on NAFLD and different diets are based either on epidemiological studies, or meta-analysis, which are not controlled evidences; in most of the cases, they are biased on test-subject type and their lifestyles. The highest success in reverting NAFLD can be attributed to diets based on high protein instead of carbohydrates. In this review, we discuss the impact of NAFLD on body metabolic plasticity. We also present a detailed analysis of the most recent studies that evaluate high-protein diets in NAFLD with a special focus on the liver and the skeletal muscle protein metabolisms.
Collapse
|
|
35
|
Song Z, Wang H, Yin X, Deng P, Jiang W. Application of NMR metabolomics to search for human disease biomarkers in blood. Clin Chem Lab Med 2019; 57:417-441. [PMID: 30169327 DOI: 10.1515/cclm-2018-0380] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2018] [Accepted: 07/16/2018] [Indexed: 02/05/2023]
Abstract
Recently, nuclear magnetic resonance spectroscopy (NMR)-based metabolomics analysis and multivariate statistical techniques have been incorporated into a multidisciplinary approach to profile changes in small molecules associated with the onset and progression of human diseases. The purpose of these efforts is to identify unique metabolite biomarkers in a specific human disease so as to (1) accurately predict and diagnose diseases, including separating distinct disease stages; (2) provide insights into underlying pathways in the pathogenesis and progression of the malady and (3) aid in disease treatment and evaluate the efficacy of drugs. In this review we discuss recent developments in the application of NMR-based metabolomics in searching disease biomarkers in human blood samples in the last 5 years.
Collapse
Affiliation(s)
- Zikuan Song
- Molecular Medicine Research Center, West China Hospital, Sichuan University, Chengdu, Sichuan, P.R. China.,West China School of Basic Medical Science and Forensic Medicine, Sichuan University, Chengdu, Sichuan, P.R. China
| | - Haoyu Wang
- Molecular Medicine Research Center, West China Hospital, Sichuan University, Chengdu, Sichuan, P.R. China.,West China School of Basic Medical Science and Forensic Medicine, Sichuan University, Chengdu, Sichuan, P.R. China
| | - Xiaotong Yin
- Molecular Medicine Research Center, West China Hospital, Sichuan University, Chengdu, Sichuan, P.R. China.,West China School of Basic Medical Science and Forensic Medicine, Sichuan University, Chengdu, Sichuan, P.R. China
| | - Pengchi Deng
- Analytical and Testing Center, Sichuan University, Chengdu, Sichuan, P.R. China
| | - Wei Jiang
- Molecular Medicine Research Center, West China Hospital, Sichuan University, Chengdu, Sichuan, P.R. China
| |
Collapse
|
|
36
|
Effects of Periodic Fasting on Fatty Liver Index-A Prospective Observational Study. Nutrients 2019; 11:nu11112601. [PMID: 31671589 PMCID: PMC6893587 DOI: 10.3390/nu11112601] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Revised: 10/24/2019] [Accepted: 10/28/2019] [Indexed: 02/07/2023] Open
Abstract
This prospective observational trial investigated effects and safety of periodic fasting in subjects with and without type 2 diabetes mellitus (T2DM). The primary end point was set as the change of fatty liver index (FLI) as a surrogate parameter of non-alcoholic fatty liver disease (NAFLD). Six-hundred and ninety-seven subjects (38 with T2DM) were enrolled. A baseline FLI ≥ 60 (the threshold for fatty liver) was found in 264 subjects (37.9%). The mean duration of fasting was 8.5 ± 4.0 days (range 6–38). FLI decreased significantly (−14.02 ± 11.67; p < 0.0001), with a larger effect in individuals with T2DM (−19.15 ± 11.0; p < 0.0001; p = 0.002 compared to non-diabetic subjects). Body mass index (BMI) decreased by −1.51 ± 0.82 kg/m2, and 49.9% of the subjects lost ≥5% body weight. After fasting, nearly half of the 264 subjects with FLI ≥ 60 (highest risk category) shifted to a lower category. The improvement of FLI correlated with the number of fasting days (r = −0.20, p < 0.0001) and with the magnitude of BMI reduction (r = 0.14, p = 0.0001). Periodic fasting with concomitant weight reduction leads to significant rapid improvement of FLI in subjects with and without T2DM.
Collapse
|
|
37
|
Léveillé M, Estall JL. Mitochondrial Dysfunction in the Transition from NASH to HCC. Metabolites 2019; 9:E233. [PMID: 31623280 PMCID: PMC6836234 DOI: 10.3390/metabo9100233] [Citation(s) in RCA: 64] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Revised: 09/26/2019] [Accepted: 10/11/2019] [Indexed: 02/06/2023] Open
Abstract
The liver constantly adapts to meet energy requirements of the whole body. Despite its remarkable adaptative capacity, prolonged exposure of liver cells to harmful environmental cues (such as diets rich in fat, sugar, and cholesterol) results in the development of chronic liver diseases (including non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH)) that can progress to hepatocellular carcinoma (HCC). The pathogenesis of these diseases is extremely complex, multifactorial, and poorly understood. Emerging evidence suggests that mitochondrial dysfunction or maladaptation contributes to detrimental effects on hepatocyte bioenergetics, reactive oxygen species (ROS) homeostasis, endoplasmic reticulum (ER) stress, inflammation, and cell death leading to NASH and HCC. The present review highlights the potential contribution of altered mitochondria function to NASH-related HCC and discusses how agents targeting this organelle could provide interesting treatment strategies for these diseases.
Collapse
Affiliation(s)
- Mélissa Léveillé
- Institut de Recherches Cliniques de Montréal (IRCM), Montreal, Quebec, QC H2W 1R7, Canada.
- Faculty of Medicine, University of Montreal, Montreal, Quebec, QC H3G 2M1, Canada.
| | - Jennifer L Estall
- Institut de Recherches Cliniques de Montréal (IRCM), Montreal, Quebec, QC H2W 1R7, Canada.
- Faculty of Medicine, University of Montreal, Montreal, Quebec, QC H3G 2M1, Canada.
- Division of Experimental Medicine, McGill University, Montreal, Quebec, QC H4A 3J1, Canada.
| |
Collapse
|
|
38
|
Männistö V, Kaminska D, Kärjä V, Tiainen M, de Mello VD, Hanhineva K, Soininen P, Ala-Korpela M, Pihlajamäki J. Total liver phosphatidylcholine content associates with non-alcoholic steatohepatitis and glycine N-methyltransferase expression. Liver Int 2019; 39:1895-1905. [PMID: 31199045 DOI: 10.1111/liv.14174] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Revised: 05/27/2019] [Accepted: 06/04/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Alterations in liver phosphatidylcholine (PC) metabolism have been implicated in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Although genetic variation in the phosphatidylethanolamine N-methyltransferase (PEMT) enzyme synthesizing PC has been associated with disease, the functional mechanism linking PC metabolism to the pathogenesis of non-alcoholic steatohepatitis (NASH) remains unclear. METHODS Serum PC levels and liver PC contents were measured using proton nuclear magnetic resonance (NMR) spectroscopy in 169 obese individuals [age 46.6 ± 10 (mean ± SD) years, BMI 43.3 ± 6 kg/m2 , 53 men and 116 women] with histological assessment of NAFLD; 106 of these had a distinct liver phenotype. All subjects were genotyped for PEMT rs7946 and liver mRNA expression of PEMT and glycine N-methyltransferase (GNMT) was analysed. RESULTS Liver PC content was lower in those with NASH (P = 1.8 x 10-6 ) while serum PC levels did not differ between individuals with NASH and normal liver (P = 0.591). Interestingly, serum and liver PC did not correlate (rs = -0.047, P = 0.557). Serum PC and serum cholesterol levels correlated strongly (rs = 0.866, P = 7.1 x 10-49 ), while liver PC content did not correlate with serum cholesterol (rs = 0.065, P = 0.413). Neither PEMT V175M genotype nor PEMT expression explained the association between liver PC content and NASH. Instead, liver GNMT mRNA expression was decreased in those with NASH (P = 3.8 x 10-4 ) and correlated with liver PC content (rs = 0.265, P = 0.001). CONCLUSIONS Decreased liver PC content in individuals with the NASH is independent of PEMT V175M genotype and could be partly linked to decreased GNMT expression.
Collapse
Affiliation(s)
- Ville Männistö
- Department of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland
| | - Dorota Kaminska
- Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
| | - Vesa Kärjä
- Department of Pathology, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland
| | - Mika Tiainen
- NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio, Finland
| | - Vanessa D de Mello
- Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
| | - Kati Hanhineva
- Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland.,LC-MS Metabolomics Center, Biocenter Kuopio, Kuopio, Finland
| | - Pasi Soininen
- NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio, Finland
| | - Mika Ala-Korpela
- NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio, Finland.,Systems Epidemiology, Baker Heart and Diabetes Institute, Melbourne, Vic., Australia.,Computational Medicine, Faculty of Medicine, University of Oulu and Biocenter Oulu, Oulu, Finland.,Population Health Science, Bristol Medical School, University of Bristol, Bristol, UK.,Medical Research Council Integrative Epidemiology Unit at the University of Bristol, Bristol, UK.,Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Faculty of Medicine, Nursing and Health Sciences, The Alfred Hospital, Monash University, Melbourne, Vic., Australia
| | - Jussi Pihlajamäki
- Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland.,Clinical Nutrition and Obesity Center, Kuopio University Hospital, Kuopio, Finland
| |
Collapse
|
|
39
|
Watt MJ, Miotto PM, De Nardo W, Montgomery MK. The Liver as an Endocrine Organ-Linking NAFLD and Insulin Resistance. Endocr Rev 2019; 40:1367-1393. [PMID: 31098621 DOI: 10.1210/er.2019-00034] [Citation(s) in RCA: 380] [Impact Index Per Article: 63.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2019] [Accepted: 04/04/2019] [Indexed: 02/06/2023]
Abstract
The liver is a dynamic organ that plays critical roles in many physiological processes, including the regulation of systemic glucose and lipid metabolism. Dysfunctional hepatic lipid metabolism is a cause of nonalcoholic fatty liver disease (NAFLD), the most common chronic liver disorder worldwide, and is closely associated with insulin resistance and type 2 diabetes. Through the use of advanced mass spectrometry "omics" approaches and detailed experimentation in cells, mice, and humans, we now understand that the liver secretes a wide array of proteins, metabolites, and noncoding RNAs (miRNAs) and that many of these secreted factors exert powerful effects on metabolic processes both in the liver and in peripheral tissues. In this review, we summarize the rapidly evolving field of "hepatokine" biology with a particular focus on delineating previously unappreciated communication between the liver and other tissues in the body. We describe the NAFLD-induced changes in secretion of liver proteins, lipids, other metabolites, and miRNAs, and how these molecules alter metabolism in liver, muscle, adipose tissue, and pancreas to induce insulin resistance. We also synthesize the limited information that indicates that extracellular vesicles, and in particular exosomes, may be an important mechanism for intertissue communication in normal physiology and in promoting metabolic dysregulation in NAFLD.
Collapse
Affiliation(s)
- Matthew J Watt
- Department of Physiology, University of Melbourne, Melbourne, Victoria, Australia
| | - Paula M Miotto
- Department of Physiology, University of Melbourne, Melbourne, Victoria, Australia
| | - William De Nardo
- Department of Physiology, University of Melbourne, Melbourne, Victoria, Australia
| | | |
Collapse
|
|
40
|
Hartley A, Santos Ferreira DL, Anderson EL, Lawlor DA. Metabolic profiling of adolescent non-alcoholic fatty liver disease. Wellcome Open Res 2019; 3:166. [PMID: 30687796 PMCID: PMC6338132 DOI: 10.12688/wellcomeopenres.14974.1] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/19/2018] [Indexed: 02/02/2023] Open
Abstract
Background: Adolescent non-alcoholic fatty liver disease (NAFLD) is associated with cardiometabolic risk factors. The association between adolescent NAFLD and a wide range of metabolic biomarkers is unclear. We have attempted to determine the differences in metabolic profile of adolescents with and without markers of NAFLD. Methods: We performed cross-sectional analyses in a sample of 3,048 participants from the Avon Longitudinal Study of Parents and Children at age 17. We used three indicators of NAFLD: ALT >40 U/l; AST >40 U/l and ultrasound scan-assessed steatosis. Associations between each measure of NAFLD and 154 metabolic traits, assessed by Nuclear Magnetic Resonance, were analyzed by multivariable linear regression, adjusting for age, sex and BMI. Results: All three indicators of NAFLD were associated with ~0.5 standard deviation (SD) greater concentrations of all extremely large to small very low-density lipoproteins (VLDL) measures. ALT >40U/l was associated with ~0.5SD greater concentrations of very small VLDLs, intermediate-density lipoproteins and low-density lipoproteins. Concentrations of most cholesterols, including remnant cholesterol, all triglycerides and monounsaturated fatty acids, in addition to glycoprotein acetyls (inflammatory marker), were also higher in participants with NAFLD. Conclusions: We have identified differing metabolic profiles between adolescents with and without indicators of NAFLD. These results provide the foundations for future research to determine whether these differences persist and result in adverse future cardiometabolic health.
Collapse
Affiliation(s)
- April Hartley
- Musculoskeletal Research Unit, Translational Health Sciences, University of Bristol, Bristol, BS10 5NB, UK,MRC Integrative Epidemiology Unit, University of Bristol, Bristol, BS8 2BN, UK,Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, BS8 2BN, UK,
| | - Diana L. Santos Ferreira
- MRC Integrative Epidemiology Unit, University of Bristol, Bristol, BS8 2BN, UK,Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, BS8 2BN, UK
| | - Emma L. Anderson
- MRC Integrative Epidemiology Unit, University of Bristol, Bristol, BS8 2BN, UK,Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, BS8 2BN, UK
| | - Debbie A. Lawlor
- MRC Integrative Epidemiology Unit, University of Bristol, Bristol, BS8 2BN, UK,Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, BS8 2BN, UK
| |
Collapse
|
|
41
|
Hartley A, Santos Ferreira DL, Anderson EL, Lawlor DA. Metabolic profiling of adolescent non-alcoholic fatty liver disease. Wellcome Open Res 2019; 3:166. [PMID: 30687796 PMCID: PMC6338132 DOI: 10.12688/wellcomeopenres.14974.2] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/09/2019] [Indexed: 02/02/2023] Open
Abstract
Background: Adolescent non-alcoholic fatty liver disease (NAFLD) is associated with cardiometabolic risk factors. The association between adolescent NAFLD and a wide range of metabolic biomarkers is unclear. We have attempted to determine the differences in metabolic profile of adolescents with and without markers of NAFLD. Methods: We performed cross-sectional analyses in a sample of 3,048 participants from the Avon Longitudinal Study of Parents and Children at age 17. We used three indicators of NAFLD: ALT >40 U/l; AST >40 U/l and ultrasound scan-assessed steatosis. Associations between each measure of NAFLD and 154 metabolic traits, assessed by Nuclear Magnetic Resonance, were analyzed by multivariable linear regression, adjusting for age, sex and BMI. Results: All three indicators of NAFLD were associated with ~0.5 standard deviation (SD) greater concentrations of all extremely large to small very low-density lipoproteins (VLDL) measures. ALT >40U/l was associated with ~0.5SD greater concentrations of very small VLDLs, intermediate-density lipoproteins and low-density lipoproteins. Concentrations of most cholesterols, including remnant cholesterol, all triglycerides and monounsaturated fatty acids, in addition to glycoprotein acetyls (inflammatory marker), were also higher in participants with NAFLD. Conclusions: We have identified differing metabolic profiles between adolescents with and without indicators of NAFLD. These results provide the foundations for future research to determine whether these differences persist and result in adverse future cardiometabolic health.
Collapse
Affiliation(s)
- April Hartley
- Musculoskeletal Research Unit, Translational Health Sciences, University of Bristol, Bristol, BS10 5NB, UK,MRC Integrative Epidemiology Unit, University of Bristol, Bristol, BS8 2BN, UK,Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, BS8 2BN, UK,
| | - Diana L. Santos Ferreira
- MRC Integrative Epidemiology Unit, University of Bristol, Bristol, BS8 2BN, UK,Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, BS8 2BN, UK
| | - Emma L. Anderson
- MRC Integrative Epidemiology Unit, University of Bristol, Bristol, BS8 2BN, UK,Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, BS8 2BN, UK
| | - Debbie A. Lawlor
- MRC Integrative Epidemiology Unit, University of Bristol, Bristol, BS8 2BN, UK,Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, BS8 2BN, UK
| |
Collapse
|
|
42
|
Stec DE, Gordon DM, Hipp JA, Hong S, Mitchell ZL, Franco NR, Robison JW, Anderson CD, Stec DF, Hinds TD. Loss of hepatic PPARα promotes inflammation and serum hyperlipidemia in diet-induced obesity. Am J Physiol Regul Integr Comp Physiol 2019; 317:R733-R745. [PMID: 31483154 DOI: 10.1152/ajpregu.00153.2019] [Citation(s) in RCA: 66] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
Agonists for PPARα are used clinically to reduce triglycerides and improve high-density lipoprotein (HDL) cholesterol levels in patients with hyperlipidemia. Whether the mechanism of PPARα activation to lower serum lipids occurs in the liver or other tissues is unknown. To determine the function of hepatic PPARα on lipid profiles in diet-induced obese mice, we placed hepatocyte-specific peroxisome proliferator-activated receptor-α (PPARα) knockout (PparaHepKO) and wild-type (Pparafl/fl) mice on high-fat diet (HFD) or normal fat diet (NFD) for 12 wk. There was no significant difference in weight gain, percent body fat mass, or percent body lean mass between the groups of mice in response to HFD or NFD. Interestingly, the PparaHepKO mice on HFD had worsened hepatic inflammation and a significant shift in the proinflammatory M1 macrophage population. These changes were associated with higher hepatic fat mass and decreased hepatic lean mass in the PparαHepKO on HFD but not in NFD as measured by Oil Red O and noninvasive EchoMRI analysis (31.1 ± 2.8 vs. 20.2 ± 1.5, 66.6 ± 2.5 vs. 76.4 ± 1.5%, P < 0.05). We did find that this was related to significantly reduced peroxisomal gene function and lower plasma β-hydroxybutyrate in the PparaHepKO on HFD, indicative of reduced metabolism of fats in the liver. Together, these provoked higher plasma triglyceride and apolipoprotein B100 levels in the PparaHepKO mice compared with Pparafl/fl on HFD. These data indicate that hepatic PPARα functions to control inflammation and liver triglyceride accumulation that prevent hyperlipidemia.
Collapse
Affiliation(s)
- David E Stec
- Department of Physiology & Biophysics, Mississippi Center for Obesity Research, University of Mississippi Medical Center, Jackson, Mississippi
| | - Darren M Gordon
- Department of Physiology and Pharmacology, University of Toledo College of Medicine, Toledo, Ohio
| | - Jennifer A Hipp
- Department of Pathology, University of Toledo College of Medicine, Toledo, Ohio
| | - Stephen Hong
- Department of Physiology and Pharmacology, University of Toledo College of Medicine, Toledo, Ohio
| | - Zachary L Mitchell
- Department of Physiology & Biophysics, Mississippi Center for Obesity Research, University of Mississippi Medical Center, Jackson, Mississippi
| | - Natalia R Franco
- Department of Physiology & Biophysics, Mississippi Center for Obesity Research, University of Mississippi Medical Center, Jackson, Mississippi
| | - J Walker Robison
- Department of Physiology & Biophysics, Mississippi Center for Obesity Research, University of Mississippi Medical Center, Jackson, Mississippi
| | - Christopher D Anderson
- Department of Surgery and Medicine, University of Mississippi Medical Center, Jackson, Mississippi
| | - Donald F Stec
- Small Molecule NMR Facility Core, Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee
| | - Terry D Hinds
- Department of Physiology and Pharmacology, University of Toledo College of Medicine, Toledo, Ohio
| |
Collapse
|
|
43
|
Benhammou JN, Ko A, Alvarez M, Kaikkonen MU, Rankin C, Garske KM, Padua D, Bhagat Y, Kaminska D, Kärjä V, Pihlajamäki J, Pisegna JR, Pajukanta P. Novel Lipid Long Intervening Noncoding RNA, Oligodendrocyte Maturation-Associated Long Intergenic Noncoding RNA, Regulates the Liver Steatosis Gene Stearoyl-Coenzyme A Desaturase As an Enhancer RNA. Hepatol Commun 2019; 3:1356-1372. [PMID: 31592021 PMCID: PMC6771395 DOI: 10.1002/hep4.1413] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2019] [Accepted: 07/10/2019] [Indexed: 12/15/2022] Open
Abstract
The global obesity epidemic is driving the concomitant rise in nonalcoholic fatty liver disease (NAFLD). To identify new genes involved in central liver functions, we examined liver RNA‐sequence data from 259 patients who underwent morbidly obese bariatric surgery. Of these patients, 84 had normal liver histology, 40 simple steatosis, 43 nonalcoholic steatohepatitis, and the remaining 92 patients had varying degrees of NAFLD based on liver histology. We discovered oligodendrocyte maturation‐associated long intergenic noncoding RNA (OLMALINC), a long intervening noncoding RNA (lincRNA) in a human liver co‐expression network (n = 75 genes) that was strongly associated with statin use and serum triglycerides (TGs). OLMALINC liver expression was highly correlated with the expression of known cholesterol biosynthesis genes and stearoyl‐coenzyme A desaturase (SCD). SCD is the rate‐limiting enzyme in monounsaturated fatty acids and a key TG gene that is known to be up‐regulated in liver steatosis and NAFLD and resides adjacent to OLMALINC on the human chromosome 10q24.31. Next, we functionally demonstrated that OLMALINC regulates SCD as an enhancer‐RNA (eRNA), thus describing the first lincRNA that functions as an eRNA to regulate lipid metabolism. Specifically, we show that OLMALINC promotes liver expression of SCD in cis through regional chromosomal DNA–DNA looping interactions. Conclusion: The primate‐specific lincRNA OLMALINC is a novel epigenetic regulator of the key TG and NAFLD gene SCD.
Collapse
Affiliation(s)
- Jihane N Benhammou
- Vatche and Tamar Manoukian Division of Digestive Diseases University of California Los Angeles Los Angeles CA.,Department of Human Genetics David Geffen School of Medicine at University of California Los Angeles Los Angeles CA.,Division of Gastroenterology, Hepatology, and Parenteral Nutrition, Department of Medicine Veterans Administration Greater Los Angeles Healthcare System Los Angeles CA
| | - Arthur Ko
- Department of Medicine David Geffen School of Medicine at University of California Los Angeles Los Angeles CA
| | - Marcus Alvarez
- Department of Human Genetics David Geffen School of Medicine at University of California Los Angeles Los Angeles CA
| | - Minna U Kaikkonen
- Institute of Public Health and Clinical Nutrition University of Eastern Finland Kuopio Finland
| | - Carl Rankin
- Vatche and Tamar Manoukian Division of Digestive Diseases University of California Los Angeles Los Angeles CA
| | - Kristina M Garske
- Department of Human Genetics David Geffen School of Medicine at University of California Los Angeles Los Angeles CA
| | - David Padua
- Vatche and Tamar Manoukian Division of Digestive Diseases University of California Los Angeles Los Angeles CA.,Division of Gastroenterology, Hepatology, and Parenteral Nutrition, Department of Medicine Veterans Administration Greater Los Angeles Healthcare System Los Angeles CA
| | - Yash Bhagat
- Department of Human Genetics David Geffen School of Medicine at University of California Los Angeles Los Angeles CA
| | - Dorota Kaminska
- Department of Human Genetics David Geffen School of Medicine at University of California Los Angeles Los Angeles CA.,Institute of Public Health and Clinical Nutrition University of Eastern Finland Kuopio Finland
| | - Vesa Kärjä
- Department of Clinical Pathology Kuopio University Hospital Kuopio Finland
| | - Jussi Pihlajamäki
- Institute of Public Health and Clinical Nutrition University of Eastern Finland Kuopio Finland.,Clinical Nutrition and Obesity Center Kuopio University Hospital Kuopio Finland
| | - Joseph R Pisegna
- Department of Human Genetics David Geffen School of Medicine at University of California Los Angeles Los Angeles CA.,Division of Gastroenterology, Hepatology, and Parenteral Nutrition, Department of Medicine Veterans Administration Greater Los Angeles Healthcare System Los Angeles CA
| | - Päivi Pajukanta
- Department of Human Genetics David Geffen School of Medicine at University of California Los Angeles Los Angeles CA.,Bioinformatics Interdepartmental Program University of California Los Angeles Los Angeles CA.,Institute for Precision Health of University of California Los Angeles Los Angeles CA
| |
Collapse
|
|
44
|
Geisler CE, Ghimire S, Bogan RL, Renquist BJ. Role of ketone signaling in the hepatic response to fasting. Am J Physiol Gastrointest Liver Physiol 2019; 316:G623-G631. [PMID: 30767679 PMCID: PMC6580236 DOI: 10.1152/ajpgi.00415.2017] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Ketosis is a metabolic adaptation to fasting, nonalcoholic fatty liver disease (NAFLD), and prolonged exercise. β-OH butyrate acts as a transcriptional regulator and at G protein-coupled receptors to modulate cellular signaling pathways in a hormone-like manner. While physiological ketosis is often adaptive, chronic hyperketonemia may contribute to the metabolic dysfunction of NAFLD. To understand how β-OH butyrate signaling affects hepatic metabolism, we compared the hepatic fasting response in control and 3-hydroxy-3-methylglutaryl-CoA synthase II (HMGCS2) knockdown mice that are unable to elevate β-OH butyrate production. To establish that rescue of ketone metabolic/endocrine signaling would restore the normal hepatic fasting response, we gave intraperitoneal injections of β-OH butyrate (5.7 mmol/kg) to HMGCS2 knockdown and control mice every 2 h for the final 9 h of a 16-h fast. In hypoketonemic, HMGCS2 knockdown mice, fasting more robustly increased mRNA expression of uncoupling protein 2 (UCP2), a protein critical for supporting fatty acid oxidation and ketogenesis. In turn, exogenous β-OH butyrate administration to HMGCS2 knockdown mice decreased fasting UCP2 mRNA expression to that observed in control mice. Also supporting feedback at the transcriptional level, β-OH butyrate lowered the fasting-induced expression of HMGCS2 mRNA in control mice. β-OH butyrate also regulates the glycemic response to fasting. The fast-induced fall in serum glucose was absent in HMGCS2 knockdown mice but was restored by β-OH butyrate administration. These data propose that endogenous β-OH butyrate signaling transcriptionally regulates hepatic fatty acid oxidation and ketogenesis, while modulating glucose tolerance. NEW & NOTEWORTHY Ketogenesis regulates whole body glucose metabolism and β-OH butyrate produced by the liver feeds back to inhibit hepatic β-oxidation and ketogenesis during fasting.
Collapse
Affiliation(s)
- Caroline E. Geisler
- School of Animal and Comparative Biomedical Science, University of Arizona, Tucson, Arizona
| | - Susma Ghimire
- School of Animal and Comparative Biomedical Science, University of Arizona, Tucson, Arizona
| | - Randy L. Bogan
- School of Animal and Comparative Biomedical Science, University of Arizona, Tucson, Arizona
| | - Benjamin J. Renquist
- School of Animal and Comparative Biomedical Science, University of Arizona, Tucson, Arizona
| |
Collapse
|
|
45
|
Changes of Circulating Extracellular Vesicles from the Liver after Roux-en-Y Bariatric Surgery. Int J Mol Sci 2019; 20:ijms20092153. [PMID: 31052333 PMCID: PMC6539504 DOI: 10.3390/ijms20092153] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2019] [Revised: 04/23/2019] [Accepted: 04/26/2019] [Indexed: 12/19/2022] Open
Abstract
Circulating extracellular vesicles are small particles enclosed by a phospholipid bilayer. Vesicles deriving directly from the cellular membrane by an active budding process retain cell origin specific proteins and RNA. These vesicles carry pathophysiological information from their parental cell and hold the potential to allow analysis of organs without the need for a biopsy. We included in our study 27 patients undergoing bariatric surgery. Hepatic extracellular vesicles were determined by flow cytometry. mRNA specific for hepatic cellular origin was determined in the extracellular vesicle fraction using qPCR. Surgery led to a massive reduction of weight and overall hepatic stress as determined by alanine transaminase (ALT), aspartate transaminase (AST) and γ-glutamyltransferase (GGT). Total extracellular vesicle numbers were reduced after bariatric surgery. Liver specific vesicles identified by HepPar1 or asialoglycoprotein receptor (ASGPR) were significantly reduced after bariatric surgery in both AnnexinV+ and AnnexinV− subgroups. When analyzing circulating liver-specific mRNAs, we found reduced levels of these mRNAs after surgery even though total circulating RNA remained unchanged. We conclude that circulating hepatic extracellular vesicles are detectable in samples from patients undergoing gastric bypass surgery. These vesicles are reduced after a reduction of hepatic stress also observed with classic liver enzyme measurements. We conclude that ASGPR or HepPar positive vesicles hold the potential to serve as liver specific vesicle markers.
Collapse
|
|
46
|
Fletcher JA, Deja S, Satapati S, Fu X, Burgess SC, Browning JD. Impaired ketogenesis and increased acetyl-CoA oxidation promote hyperglycemia in human fatty liver. JCI Insight 2019; 5:127737. [PMID: 31012869 DOI: 10.1172/jci.insight.127737] [Citation(s) in RCA: 111] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent, and potentially morbid, disease that affects one-third of the U.S. population. Normal liver safely accommodates lipid excess during fasting or carbohydrate restriction by increasing their oxidation to acetyl-CoA and ketones, yet lipid excess during NAFLD leads to hyperglycemia and, in some, steatohepatitis. To examine potential mechanisms, flux through pathways of hepatic oxidative metabolism and gluconeogenesis were studied using five simultaneous stable isotope tracers in ketotic (24-hour fast) individuals with a wide range of hepatic triglyceride contents (0-52%). Ketogenesis was progressively impaired as hepatic steatosis and glycemia worsened. Conversely, the alternative pathway for acetyl-CoA metabolism, oxidation in the tricarboxylic (TCA) cycle, was upregulated in NAFLD as ketone production diminished and positively correlated with rates of gluconeogenesis and plasma glucose concentrations. Increased respiration and energy generation that occurred in liver when β-oxidation and TCA cycle activity were coupled may explain these findings, inasmuch as oxygen consumption was higher during fatty liver and highly correlated with gluconeogenesis. These findings demonstrate that increased glucose production and hyperglycemia in NAFLD is not a consequence of acetyl-CoA production per se, but how acetyl-CoA is further metabolized in liver.
Collapse
Affiliation(s)
| | | | | | | | | | - Jeffrey D Browning
- Advanced Imaging Research Center.,Department of Internal Medicine, and.,Department of Clinical Nutrition, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA
| |
Collapse
|
|
47
|
Sliz E, Sebert S, Würtz P, Kangas AJ, Soininen P, Lehtimäki T, Kähönen M, Viikari J, Männikkö M, Ala-Korpela M, Raitakari OT, Kettunen J. NAFLD risk alleles in PNPLA3, TM6SF2, GCKR and LYPLAL1 show divergent metabolic effects. Hum Mol Genet 2019; 27:2214-2223. [PMID: 29648650 PMCID: PMC5985737 DOI: 10.1093/hmg/ddy124] [Citation(s) in RCA: 100] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2018] [Accepted: 04/04/2018] [Indexed: 12/15/2022] Open
Abstract
Fatty liver has been associated with unfavourable metabolic changes in circulation. To provide insights in fatty liver-related metabolic deviations, we compared metabolic association profile of fatty liver versus metabolic association profiles of genotypes increasing the risk of non-alcoholic fatty liver disease (NAFLD). The cross-sectional associations of ultrasound-ascertained fatty liver with 123 metabolic measures were determined in 1810 (Nfatty liver = 338) individuals aged 34–49 years from The Cardiovascular Risk in Young Finns Study. The association profiles of NAFLD-risk alleles in PNPLA3, TM6SF2, GCKR, and LYPLAL1 with the corresponding metabolic measures were obtained from a publicly available metabolomics GWAS including up to 24 925 Europeans. The risk alleles showed different metabolic effects: PNPLA3 rs738409-G, the strongest genetic NAFLD risk factor, did not associate with metabolic changes. Metabolic effects of GCKR rs1260326-T were comparable in many respects to the fatty liver associations. Metabolic effects of LYPLAL1 rs12137855-C were similar, but statistically less robust, to the effects of GCKR rs1260326-T. TM6SF2 rs58542926-T displayed opposite metabolic effects when compared with the fatty liver associations. The metabolic effects of the risk alleles highlight heterogeneity of the molecular pathways leading to fatty liver and suggest that the fatty liver-related changes in the circulating lipids and metabolites may vary depending on the underlying pathophysiological mechanism. Despite the robust cross-sectional associations on population level, the present results showing neutral or cardioprotective metabolic effects for some of the NAFLD risk alleles advocate that hepatic lipid accumulation by itself may not increase the level of circulating lipids or other metabolites.
Collapse
Affiliation(s)
- Eeva Sliz
- Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland.,Biocenter Oulu, University of Oulu, Oulu, Finland
| | - Sylvain Sebert
- Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland.,Biocenter Oulu, University of Oulu, Oulu, Finland.,Department of Genomics of Complex Diseases, School of Public Health, Imperial College London, London, UK
| | - Peter Würtz
- Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland.,Nightingale Health Ltd., Helsinki, Finland
| | | | - Pasi Soininen
- Nightingale Health Ltd., Helsinki, Finland.,NMR Metabolomics Laboratory, School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland
| | - Terho Lehtimäki
- Fimlab Laboratories, Department of Clinical Chemistry, Finnish Cardiovascular Research Center Tampere, Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland
| | - Mika Kähönen
- Department of Clinical Physiology, Tampere University Hospital and Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland
| | - Jorma Viikari
- Division of Medicine, Department of Medicine, University of Turku, Turku University Hospital, Turku, Finland
| | - Minna Männikkö
- Northern Finland Birth Cohorts, Faculty of Medicine, University of Oulu, Oulu, Finland
| | - Mika Ala-Korpela
- Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland.,Biocenter Oulu, University of Oulu, Oulu, Finland.,NMR Metabolomics Laboratory, School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland.,Computational Medicine, Faculty of Medicine, University of Oulu, Oulu, Finland.,Population Health Science, Bristol Medical School, University of Bristol and Medical Research Council Integrative Epidemiology Unit at the University of Bristol, Bristol, UK.,Systems Epidemiology, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia.,Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Faculty of Medicine, Nursing and Health Sciences, The Alfred Hospital, Monash University, Melbourne, VIC, Australia
| | - Olli T Raitakari
- Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland.,Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland
| | - Johannes Kettunen
- Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland.,Biocenter Oulu, University of Oulu, Oulu, Finland.,Computational Medicine, Faculty of Medicine, University of Oulu, Oulu, Finland.,Population Health Science, Bristol Medical School, University of Bristol and Medical Research Council Integrative Epidemiology Unit at the University of Bristol, Bristol, UK
| |
Collapse
|
|
48
|
Würtz P, Kangas AJ, Soininen P, Lawlor DA, Davey Smith G, Ala-Korpela M. Quantitative Serum Nuclear Magnetic Resonance Metabolomics in Large-Scale Epidemiology: A Primer on -Omic Technologies. Am J Epidemiol 2017; 186:1084-1096. [PMID: 29106475 PMCID: PMC5860146 DOI: 10.1093/aje/kwx016] [Citation(s) in RCA: 366] [Impact Index Per Article: 45.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2016] [Accepted: 01/19/2017] [Indexed: 12/13/2022] Open
Abstract
Detailed metabolic profiling in large-scale epidemiologic studies has uncovered novel biomarkers for cardiometabolic diseases and clarified the molecular associations of established risk factors. A quantitative metabolomics platform based on nuclear magnetic resonance spectroscopy has found widespread use, already profiling over 400,000 blood samples. Over 200 metabolic measures are quantified per sample; in addition to many biomarkers routinely used in epidemiology, the method simultaneously provides fine-grained lipoprotein subclass profiling and quantification of circulating fatty acids, amino acids, gluconeogenesis-related metabolites, and many other molecules from multiple metabolic pathways. Here we focus on applications of magnetic resonance metabolomics for quantifying circulating biomarkers in large-scale epidemiology. We highlight the molecular characterization of risk factors, use of Mendelian randomization, and the key issues of study design and analyses of metabolic profiling for epidemiology. We also detail how integration of metabolic profiling data with genetics can enhance drug development. We discuss why quantitative metabolic profiling is becoming widespread in epidemiology and biobanking. Although large-scale applications of metabolic profiling are still novel, it seems likely that comprehensive biomarker data will contribute to etiologic understanding of various diseases and abilities to predict disease risks, with the potential to translate into multiple clinical settings.
Collapse
Affiliation(s)
- Peter Würtz
- Correspondence to Dr. Peter Würtz, Computational Medicine, Faculty of Medicine, Aapistie 5A, P.O. Box 5000, FI-90014 University of Oulu, Finland (e-mail: ); or Dr. Mika Ala-Korpela, Computational Medicine, Faculty of Medicine, Aapistie 5A, P.O. Box 5000, FI-90014 University of Oulu, Finland (e-mail: )
| | | | | | | | | | - Mika Ala-Korpela
- Correspondence to Dr. Peter Würtz, Computational Medicine, Faculty of Medicine, Aapistie 5A, P.O. Box 5000, FI-90014 University of Oulu, Finland (e-mail: ); or Dr. Mika Ala-Korpela, Computational Medicine, Faculty of Medicine, Aapistie 5A, P.O. Box 5000, FI-90014 University of Oulu, Finland (e-mail: )
| |
Collapse
|
|
49
|
Guo F, Zi T, Liu L, Feng R, Sun C. A 1H-NMR based metabolomics study of the intervention effect of mangiferin on hyperlipidemia hamsters induced by a high-fat diet. Food Funct 2017; 8:2455-2464. [PMID: 28617510 DOI: 10.1039/c7fo00081b] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/31/2025]
Abstract
It has been demonstrated that mangiferin can ameliorate hypertriglyceridemia by modulating the expression levels of genes involved in lipid metabolism in animal experiments, but its effects on the serum metabolic fingerprinting of hyperlipidemia animal models have not been reported. Thus, a NMR-based metabolomics approach was conducted to explore the effects of mangiferin on hyperlipidemia hamsters and to gain a better understanding of the involved metabolic pathways. Hamsters fed with a high-fat diet were orally administered with mangiferin 150 mg per kg BW once a day for 8 weeks. Serum samples were analysed by 1H NMR, and multivariate statistical analysis was applied to the data to identify potential biomarkers. In total, 20 discriminating metabolites were identified. It turned out that mangiferin administration can partly reverse the metabolism disorders induced by a high-fat diet and exerted a good anti-hypertriglyceridemia effect. Mangiferin ameliorated hyperlipidemia by intervening in some major metabolic pathways, involving glycolysis, the TCA cycle, synthesis of ketone bodies, and BCAAs as well as choline and lipid metabolism. These findings provided new essential information on the effects of mangiferin and demonstrated the great potential of this nutrimetabolomics approach.
Collapse
Affiliation(s)
- Fuchuan Guo
- Department of Nutrition and Food Safety, School of Public Health, Fujian Medical University, FuZhou, 350122, China.
| | | | | | | | | |
Collapse
|
|
50
|
Geisler CE, Renquist BJ. Hepatic lipid accumulation: cause and consequence of dysregulated glucoregulatory hormones. J Endocrinol 2017; 234:R1-R21. [PMID: 28428362 DOI: 10.1530/joe-16-0513] [Citation(s) in RCA: 129] [Impact Index Per Article: 16.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2017] [Accepted: 04/20/2017] [Indexed: 12/11/2022]
Abstract
Fatty liver can be diet, endocrine, drug, virus or genetically induced. Independent of cause, hepatic lipid accumulation promotes systemic metabolic dysfunction. By acting as peroxisome proliferator-activated receptor (PPAR) ligands, hepatic non-esterified fatty acids upregulate expression of gluconeogenic, beta-oxidative, lipogenic and ketogenic genes, promoting hyperglycemia, hyperlipidemia and ketosis. The typical hormonal environment in fatty liver disease consists of hyperinsulinemia, hyperglucagonemia, hypercortisolemia, growth hormone deficiency and elevated sympathetic tone. These endocrine and metabolic changes further encourage hepatic steatosis by regulating adipose tissue lipolysis, liver lipid uptake, de novo lipogenesis (DNL), beta-oxidation, ketogenesis and lipid export. Hepatic lipid accumulation may be induced by 4 separate mechanisms: (1) increased hepatic uptake of circulating fatty acids, (2) increased hepatic de novo fatty acid synthesis, (3) decreased hepatic beta-oxidation and (4) decreased hepatic lipid export. This review will discuss the hormonal regulation of each mechanism comparing multiple physiological models of hepatic lipid accumulation. Nonalcoholic fatty liver disease (NAFLD) is typified by increased hepatic lipid uptake, synthesis, oxidation and export. Chronic hepatic lipid signaling through PPARgamma results in gene expression changes that allow concurrent activity of DNL and beta-oxidation. The importance of hepatic steatosis in driving systemic metabolic dysfunction is highlighted by the common endocrine and metabolic disturbances across many conditions that result in fatty liver. Understanding the mechanisms underlying the metabolic dysfunction that develops as a consequence of hepatic lipid accumulation is critical to identifying points of intervention in this increasingly prevalent disease state.
Collapse
Affiliation(s)
- Caroline E Geisler
- School of Animal and Comparative Biomedical SciencesUniversity of Arizona, Tucson, Arizona, USA
| | - Benjamin J Renquist
- School of Animal and Comparative Biomedical SciencesUniversity of Arizona, Tucson, Arizona, USA
| |
Collapse
|