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Marino L, Kim A, Ni B, Celi FS. Thyroid hormone action and liver disease, a complex interplay. Hepatology 2025; 81:651-669. [PMID: 37535802 PMCID: PMC11737129 DOI: 10.1097/hep.0000000000000551] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Accepted: 07/05/2023] [Indexed: 08/05/2023]
Abstract
Thyroid hormone action is involved in virtually all physiological processes. It is well known that the liver and thyroid are intimately linked, with thyroid hormone playing important roles in de novo lipogenesis, beta-oxidation (fatty acid oxidation), cholesterol metabolism, and carbohydrate metabolism. Clinical and mechanistic research studies have shown that thyroid hormone can be involved in chronic liver diseases, including alcohol-associated or NAFLD and HCC. Thyroid hormone action and synthetic thyroid hormone analogs can exert beneficial actions in terms of lowering lipids, preventing chronic liver disease and as liver anticancer agents. More recently, preclinical and clinical studies have indicated that some analogs of thyroid hormone could also play a role in the treatment of liver disease. These synthetic molecules, thyromimetics, can modulate lipid metabolism, particularly in NAFLD/NASH. In this review, we first summarize the thyroid hormone signaling axis in the context of liver biology, then we describe the changes in thyroid hormone signaling in liver disease and how liver diseases affect the thyroid hormone homeostasis, and finally we discuss the use of thyroid hormone-analog for the treatment of liver disease.
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Affiliation(s)
- Luigi Marino
- Department of Medicine, UConn Health, University of Connecticut, Farmington, Connecticut, USA
| | - Adam Kim
- Division of Gastroenterology and Hepatology, Department of Medicine, UConn Health, University of Connecticut, Farmington, Connecticut, USA
| | - Bin Ni
- Alliance Pharma, Philadelphia, Pennsylvania, USA
| | - Francesco S. Celi
- Department of Medicine, UConn Health, University of Connecticut, Farmington, Connecticut, USA
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Musso G, Saba F, Cassader M, Gambino R. Lipidomics in pathogenesis, progression and treatment of nonalcoholic steatohepatitis (NASH): Recent advances. Prog Lipid Res 2023; 91:101238. [PMID: 37244504 DOI: 10.1016/j.plipres.2023.101238] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2023] [Revised: 05/20/2023] [Accepted: 05/21/2023] [Indexed: 05/29/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease affecting up to 30% of the general adult population. NAFLD encompasses a histological spectrum ranging from pure steatosis to non-alcoholic steatohepatitis (NASH). NASH can progress to cirrhosis and is becoming the most common indication for liver transplantation, as a result of increasing disease prevalence and of the absence of approved treatments. Lipidomic readouts of liver blood and urine samples from experimental models and from NASH patients disclosed an abnormal lipid composition and metabolism. Collectively, these changes impair organelle function and promote cell damage, necro-inflammation and fibrosis, a condition termed lipotoxicity. We will discuss the lipid species and metabolic pathways leading to NASH development and progression to cirrhosis, as well as and those species that can contribute to inflammation resolution and fibrosis regression. We will also focus on emerging lipid-based therapeutic opportunities, including specialized proresolving lipid molecules and macrovesicles contributing to cell-to-cell communication and NASH pathophysiology.
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Affiliation(s)
- Giovanni Musso
- Dept of Emergency Medicine, San Luigi Gonzaga University Hospital, Orbassano, Turin, Italy.
| | - Francesca Saba
- Dept. of Medical Sciences, San Giovanni Battista Hospital, University of Turin, Turin, Italy
| | - Maurizio Cassader
- Dept. of Medical Sciences, San Giovanni Battista Hospital, University of Turin, Turin, Italy
| | - Roberto Gambino
- Dept. of Medical Sciences, San Giovanni Battista Hospital, University of Turin, Turin, Italy
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Gao C, Zhang H, Nie L, He K, Li P, Wang X, Zhang Z, Xie Y, Li S, Liu G, Huang X, Deng H, Liu J, Yang X. Chrysin prevents inflammation-coinciding liver steatosis via AMPK signalling. J Pharm Pharmacol 2023:7160335. [PMID: 37167529 DOI: 10.1093/jpp/rgad041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2023] [Accepted: 04/21/2023] [Indexed: 05/13/2023]
Abstract
OBJECTIVES We aimed to elucidate the therapeutic potential of Chrysin (CN) against the high-fat diet (HFD) induced non-alcoholic fatty liver disease (NAFLD) and its mechanism. METHODS To assess the hypothesis, NAFLD was induced in C57BL/6 mice by feeding a high-fat diet for up to two months, followed by CN administration (for three months). Liver injury/toxicity, lipid deposition, inflammation and fibrosis were detected via molecular and biochemical analysis, including blood chemistry, immunoimaging and immunoblotting. Moreover, we performed proteomic analysis to illuminate Chrysin's therapeutic effects further. KEY FINDINGS CN treatment significantly reduced liver-fat accumulation and inflammation, ultimately improving obesity and liver injury in NAFLD mice. Proteomic analysis showed that CN modified the protein expression profiles in the liver, particularly improving the expression of proteins related to energy, metabolism and inflammation. Mechanistically, CN treatment increased AMP-activated protein and phosphorylated CoA (P-ACC). Concurrently, it reduced inflammation and inflammation activation by inhibiting NLRP3 expression. CONCLUSIONS In summary, CN treatment reduced lipid metabolism by AMPK and inflammasome activation by NLRP3 inhibition, ultimately improving NAFLD progression. These findings suggest that CN could be a potential treatment candidate for the NFLAD condition.
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Affiliation(s)
- Chuanyue Gao
- School of Public Health, Shanxi Medical University, Taiyuan, China
- Shenzhen Key Laboratory of Modern Toxicology, Shenzhen Medical Key Discipline of Health Toxicology (2020-2024), Shenzhen Center for Disease Control and Prevention, Shenzhen, China
| | - Huan Zhang
- Shenzhen Key Laboratory of Modern Toxicology, Shenzhen Medical Key Discipline of Health Toxicology (2020-2024), Shenzhen Center for Disease Control and Prevention, Shenzhen, China
- School of Public Health, University of South China, Hunan Hengyang, China
| | - Lulin Nie
- Shenzhen Key Laboratory of Modern Toxicology, Shenzhen Medical Key Discipline of Health Toxicology (2020-2024), Shenzhen Center for Disease Control and Prevention, Shenzhen, China
- Institute of New Drug Research and Guangzhou, Key Laboratory of Innovative Chemical Drug Research in Cardio-cerebrovascular Diseases, Jinan University College of Pharmacy, Guangzhou, 510632, China
| | - Kaiwu He
- Shenzhen Key Laboratory of Modern Toxicology, Shenzhen Medical Key Discipline of Health Toxicology (2020-2024), Shenzhen Center for Disease Control and Prevention, Shenzhen, China
| | - Peimao Li
- Medical Laboratory, Shenzhen Prevention and Treatment Center for Occupational Diseases, Luohu District, Shenzhen, China
| | - Xingxing Wang
- School of Public Health, Shanxi Medical University, Taiyuan, China
- Shenzhen Key Laboratory of Modern Toxicology, Shenzhen Medical Key Discipline of Health Toxicology (2020-2024), Shenzhen Center for Disease Control and Prevention, Shenzhen, China
| | - Zaijun Zhang
- Jinan Univ Coll Pharm Inst New Drug Res & Guangzhou Key Lab Innovat Chem Drug Res Cardio Cerebrovasc, Guangzhou, China
| | - Yongmei Xie
- State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu, China
| | - Shupeng Li
- State Key Laboratory of Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, China
| | - Gongping Liu
- Department of Pathophysiology, School of Basic Medicine and the Collaborative Innovation Center for Brain Science, Key Laboratory of Ministry of Education of China and Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xinfeng Huang
- Shenzhen Key Laboratory of Modern Toxicology, Shenzhen Medical Key Discipline of Health Toxicology (2020-2024), Shenzhen Center for Disease Control and Prevention, Shenzhen, China
| | - Huiping Deng
- Shenzhen Key Laboratory of Modern Toxicology, Shenzhen Medical Key Discipline of Health Toxicology (2020-2024), Shenzhen Center for Disease Control and Prevention, Shenzhen, China
| | - Jianjun Liu
- Shenzhen Key Laboratory of Modern Toxicology, Shenzhen Medical Key Discipline of Health Toxicology (2020-2024), Shenzhen Center for Disease Control and Prevention, Shenzhen, China
| | - Xifei Yang
- School of Public Health, Shanxi Medical University, Taiyuan, China
- Shenzhen Key Laboratory of Modern Toxicology, Shenzhen Medical Key Discipline of Health Toxicology (2020-2024), Shenzhen Center for Disease Control and Prevention, Shenzhen, China
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Inci MK, Park SH, Helsley RN, Attia SL, Softic S. Fructose impairs fat oxidation: Implications for the mechanism of western diet-induced NAFLD. J Nutr Biochem 2023; 114:109224. [PMID: 36403701 PMCID: PMC11042502 DOI: 10.1016/j.jnutbio.2022.109224] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2022] [Revised: 09/29/2022] [Accepted: 11/14/2022] [Indexed: 11/19/2022]
Abstract
Increased fructose intake from sugar-sweetened beverages and highly processed sweets is a well-recognized risk factor for the development of obesity and its complications. Fructose strongly supports lipogenesis on a normal chow diet by providing both, a substrate for lipid synthesis and activation of lipogenic transcription factors. However, the negative health consequences of dietary sugar are best observed with the concomitant intake of a HFD. Indeed, the most commonly used obesogenic research diets, such as "Western diet", contain both fructose and a high amount of fat. In spite of its common use, how the combined intake of fructose and fat synergistically supports development of metabolic complications is not fully elucidated. Here we present the preponderance of evidence that fructose consumption decreases oxidation of dietary fat in human and animal studies. We provide a detailed review of the mitochondrial β-oxidation pathway. Fructose affects hepatic activation of fatty acyl-CoAs, decreases acylcarnitine production and impairs the carnitine shuttle. Mechanistically, fructose suppresses transcriptional activity of PPARα and its target CPT1α, the rate limiting enzyme of acylcarnitine production. These effects of fructose may be, in part, mediated by protein acetylation. Acetylation of PGC1α, a co-activator of PPARα and acetylation of CPT1α, in part, account for fructose-impaired acylcarnitine production. Interestingly, metabolic effects of fructose in the liver can be largely overcome by carnitine supplementation. In summary, fructose decreases oxidation of dietary fat in the liver, in part, by impairing acylcarnitine production, offering one explanation for the synergistic effects of these nutrients on the development of metabolic complications, such as NAFLD.
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Affiliation(s)
| | - Se-Hyung Park
- Department of Pediatrics, University of Kentucky College of Medicine, Lexington, KY, USA; Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY, USA
| | - Robert N Helsley
- Department of Pediatrics, University of Kentucky College of Medicine, Lexington, KY, USA; Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY, USA; Saha Cardiovascular Research Center, University of Kentucky, Lexington, KY, USA
| | - Suzanna L Attia
- Department of Pediatrics, University of Kentucky College of Medicine, Lexington, KY, USA
| | - Samir Softic
- Department of Pediatrics, University of Kentucky College of Medicine, Lexington, KY, USA; Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY, USA; Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, MA, USA.
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Nardo WD, Miotto PM, Bayliss J, Nie S, Keenan SN, Montgomery MK, Watt MJ. Proteomic analysis reveals exercise training induced remodelling of hepatokine secretion and uncovers syndecan-4 as a regulator of hepatic lipid metabolism. Mol Metab 2022; 60:101491. [PMID: 35381388 PMCID: PMC9034320 DOI: 10.1016/j.molmet.2022.101491] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Revised: 03/22/2022] [Accepted: 03/29/2022] [Indexed: 11/04/2022] Open
Abstract
Objective Non-alcoholic fatty liver disease (NAFLD) is linked to impaired lipid metabolism and systemic insulin resistance, which is partly mediated by altered secretion of liver proteins known as hepatokines. Regular physical activity can resolve NAFLD and improve its metabolic comorbidities, however, the effects of exercise training on hepatokine secretion and the metabolic impact of exercise-regulated hepatokines in NAFLD remain unresolved. Herein, we examined the effect of endurance exercise training on hepatocyte secreted proteins with the aim of identifying proteins that regulate metabolism and reduce NAFLD severity. Methods C57BL/6 mice were fed a high-fat diet for six weeks to induce NAFLD. Mice were exercise trained for a further six weeks, while the control group remained sedentary. Hepatocytes were isolated two days after the last exercise bout, and intracellular and secreted proteins were detected using label-free mass spectrometry. Hepatocyte secreted factors were applied to skeletal muscle and liver ex vivo and insulin action and fatty acid metabolism were assessed. Syndecan-4 (SDC4), identified as an exercise-responsive hepatokine, was overexpressed in the livers of mice using adeno-associated virus. Whole-body energy homeostasis was assessed by indirect calorimetry and skeletal muscle and liver metabolism was assessed using radiometric techniques. Results Proteomics analysis detected 2657 intracellular and 1593 secreted proteins from mouse hepatocytes. Exercise training remodelled the hepatocyte proteome, with differences in 137 intracellular and 35 secreted proteins. Bioinformatic analysis of hepatocyte secreted proteins revealed enrichment of tumour suppressive proteins and proteins involved in lipid metabolism and mitochondrial function, and suppression of oncogenes and regulators of oxidative stress. Hepatocyte secreted factors from exercise trained mice improved insulin action in skeletal muscle and increased hepatic fatty acid oxidation. Hepatocyte-specific overexpression of SDC4 reduced hepatic steatosis, which was associated with reduced hepatic fatty acid uptake, and blunted pro-inflammatory and pro-fibrotic gene expression. Treating hepatocytes with recombinant ectodomain of SDC4 (secreted form) recapitulated these effects with reduced fatty acid uptake, lipid storage and lipid droplet accumulation. Conclusions Remodelling of hepatokine secretion is an adaptation to regular exercise training that induces changes in metabolism in the liver and skeletal muscle. SDC4 is a novel exercise-responsive hepatokine that decreases fatty acid uptake and reduces steatosis in the liver. By understanding the proteomic changes in hepatocytes with exercise, these findings have potential for the discovery of new therapeutic targets for NAFLD.
Exercise training remodels hepatokine secretion. Exercise regulated secreted factors improve insulin action in skeletal muscle. Syndecan-4 (SDC4) is a novel exercise-induced hepatokine. SDC4 reduces hepatic fatty acid uptake and hepatic steatosis.
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Chen M, Xiao H, Chen B, Bian Z, Kwan HY. The advantages of using Scutellaria baicalensis and its flavonoids for the management of non-viral hepatocellular carcinoma. J Funct Foods 2021. [DOI: 10.1016/j.jff.2021.104389] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
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Albhaisi S, Sanyal AJ. Gene-Environmental Interactions as Metabolic Drivers of Nonalcoholic Steatohepatitis. Front Endocrinol (Lausanne) 2021; 12:665987. [PMID: 34040583 PMCID: PMC8142267 DOI: 10.3389/fendo.2021.665987] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Accepted: 04/19/2021] [Indexed: 12/12/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) has emerged as a leading cause of chronic liver disease worldwide in the past few decades as a consequence of the global obesity epidemic and is associated with significant morbidity and mortality. NAFLD is closely associated with components of the metabolic syndrome, type 2 diabetes mellitus and cardiovascular disease, suggesting a plausible metabolic mechanistic basis. Metabolic inflexibility is considered a nidus for NAFLD pathogenesis, causing lipotoxicity, mitochondrial dysfunction and cellular stress leading to inflammation, apoptosis and fibrogenesis, thus mediating disease progression into nonalcoholic steatohepatitis (NASH) and ultimately cirrhosis. In this review, we describe they key metabolic drivers that contribute to development of NAFLD and NASH, and we explain how NASH is a metabolic disease. Understanding the metabolic basis of NASH is crucial for the prevention and treatment of this disease.
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Affiliation(s)
- Somaya Albhaisi
- Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, United States
| | - Arun J. Sanyal
- Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, United States
- *Correspondence: Arun J. Sanyal,
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Palmitate and pyruvate carbon flux in response to choline and methionine in bovine neonatal hepatocytes. Sci Rep 2020; 10:19078. [PMID: 33154483 PMCID: PMC7645801 DOI: 10.1038/s41598-020-75956-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Accepted: 10/16/2020] [Indexed: 12/20/2022] Open
Abstract
Choline and methionine may serve unique functions to alter hepatic energy metabolism. Our objective was to trace carbon flux through pathways of oxidation and glucose metabolism in bovine hepatocytes exposed to increasing concentrations of choline chloride (CC) and D,L-methionine (DLM). Primary hepatocytes were isolated from 4 Holstein calves and maintained for 24 h before treatment with CC (0, 10, 100, 1000 μmol/L) and DLM (0, 100, 300 μmol/L) in a factorial design. After 21 h, [1-14C]C16:0 or [2-14C]pyruvate was added to measure complete and incomplete oxidation, and cellular glycogen. Reactive oxygen species (ROS), cellular triglyceride (TG), and glucose and ß-hydroxybutyrate (BHB) export were quantified. Exported very-low density lipoprotein particles were isolated for untargeted lipidomics and to quantify TG. Interactions between CC and DLM, and contrasts for CC (0 vs. [10, 100, 1000 μmol/L] and linear and quadratic contrast 10, 100, 1000 μmol/L) and DLM (0 vs. [100, 300 μmol/L] and 100 vs. 300 μmol/L) were evaluated. Presence of CC increased complete oxidation of [1-14C]C16:0 and decreased BHB export. Glucose export was decreased, but cellular glycogen was increased by the presence of CC and increasing CC. Presence of CC decreased ROS and marginally decreased cellular TG. No interactions between CC and DLM were detected for these outcomes. These data suggest a hepato-protective role for CC to limit ROS and cellular TG accumulation, and to alter hepatic energy metabolism to support complete oxidation of FA and glycogen storage regardless of Met supply.
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Playing Jekyll and Hyde-The Dual Role of Lipids in Fatty Liver Disease. Cells 2020; 9:cells9102244. [PMID: 33036257 PMCID: PMC7601321 DOI: 10.3390/cells9102244] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Revised: 09/27/2020] [Accepted: 10/01/2020] [Indexed: 12/12/2022] Open
Abstract
Lipids play Jekyll and Hyde in the liver. On the one hand, the lipid-laden status of hepatic stellate cells is a hallmark of healthy liver. On the other hand, the opposite is true for lipid-laden hepatocytes—they obstruct liver function. Neglected lipid accumulation in hepatocytes can progress into hepatic fibrosis, a condition induced by the activation of stellate cells. In their resting state, these cells store substantial quantities of fat-soluble vitamin A (retinyl esters) in large lipid droplets. During activation, these lipid organelles are gradually degraded. Hence, treatment of fatty liver disease is treading a tightrope—unsophisticated targeting of hepatic lipid accumulation might trigger problematic side effects on stellate cells. Therefore, it is of great importance to gain more insight into the highly dynamic lipid metabolism of hepatocytes and stellate cells in both quiescent and activated states. In this review, part of the special issue entitled “Cellular and Molecular Mechanisms underlying the Pathogenesis of Hepatic Fibrosis 2020”, we discuss current and highly versatile aspects of neutral lipid metabolism in the pathogenesis of non-alcoholic fatty liver disease (NAFLD).
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Neuschwander-Tetri BA. Therapeutic Landscape for NAFLD in 2020. Gastroenterology 2020; 158:1984-1998.e3. [PMID: 32061596 DOI: 10.1053/j.gastro.2020.01.051] [Citation(s) in RCA: 138] [Impact Index Per Article: 27.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2019] [Revised: 01/19/2020] [Accepted: 01/21/2020] [Indexed: 12/13/2022]
Abstract
Lifestyle modifications focused on healthy eating and regular exercise are the primary recommendations for patients with nonalcoholic steatohepatitis (NASH). However, for multiple societal, psychological, physical, genetic, and epigenetic reasons, the ability of people to adopt and sustain such changes is challenging and typically not successful. To end the epidemic of NASH and prevent its complications, including cirrhosis and hepatocellular carcinoma, pharmacological interventions are now being evaluated in clinical trials. Treatments include drugs targeting energy intake, energy disposal, lipotoxic liver injury, and the resulting inflammation and fibrogenesis that lead to cirrhosis. It is likely that patients develop the phenotype of NASH by multiple mechanisms, and thus the optimal treatments of NASH will likely evolve to personalized therapy once we understand the mechanistic underpinnings of NASH in each patient. Reviewed here is the treatment landscape in this rapidly evolving field with an emphasis on drugs in Phase 2 and Phase 3 trials.
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Zeng J, Liu XL, Xin FZ, Zhao ZH, Shao YL, Yang RX, Pan Q, Fan JG. Effects and therapeutic mechanism of Yinzhihuang on steatohepatitis in rats induced by a high-fat, high-cholesterol diet. J Dig Dis 2020; 21:179-188. [PMID: 31950587 PMCID: PMC7187410 DOI: 10.1111/1751-2980.12845] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Revised: 12/04/2019] [Accepted: 01/14/2020] [Indexed: 02/05/2023]
Abstract
OBJECTIVES We aimed to investigate the therapeutic mechanism of Yinzhihuang (YZH) liquid, a traditional Chinese medicine mainly composed of extracts of four components, on nonalcoholic steatohepatitis (NASH) induced by a high-fat, high-cholesterol diet (HFHCD) in rats. METHODS Altogether 30 Sprague-Dawley rats were randomized into three groups: control, the model group (HFHCD + saline) and the treatment group (HFHCD + YZH). Liver histological features and serum biochemical parameters were assessed by the end of the 16th week. RNA sequencing and protein mass spectrometry detection were performed. The genes and proteins expressed differentially were subjected to KEGG pathway enrichment analysis and included in a network-based regulatory model. RESULTS The weight, liver and fat indices and serum alanine transaminase, aspartate transaminase and total cholesterol levels of the HFHCD + YZH group were all significantly lower than those of the HFHCD + saline group. Moreover, their hepatic steatosis, ballooning and lobular inflammation were relieved, and 64 hepatic genes and 73 hepatic proteins were found to be reversed in their expression patterns after YZH treatment (P < 0.05). The network-based regulatory model showed that these deregulated genes and proteins were mainly involved in oxidative phosphorylation, Toll-like receptor, nucleotide-binding oligomerization domain-like receptor, peroxisome proliferator-activated receptor signaling, nuclear factor-kappa B tumor necrosis factor signaling pathways and fatty acid metabolism. CONCLUSION YZH could alleviate NASH in HFHCD-fed rats by inhibiting lipogenesis, accelerating lipid β-oxidation, alleviating oxidative stress and relieving necroinflammation in the liver.
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Affiliation(s)
- Jing Zeng
- Department of GastroenterologyXinhua Hospital, Shanghai Jiao Tong University School of MedicineShanghaiChina
| | - Xiao Lin Liu
- Department of GastroenterologyThe First Affiliated Hospital of Soochow UniversitySuzhouJiangsu ProvinceChina
| | - Feng Zhi Xin
- Department of GastroenterologyXinhua Hospital, Shanghai Jiao Tong University School of MedicineShanghaiChina
| | - Ze Hua Zhao
- Department of GastroenterologyXinhua Hospital, Shanghai Jiao Tong University School of MedicineShanghaiChina
| | - You Lin Shao
- Department of GastroenterologyXinhua Hospital, Shanghai Jiao Tong University School of MedicineShanghaiChina
| | - Rui Xu Yang
- Department of GastroenterologyXinhua Hospital, Shanghai Jiao Tong University School of MedicineShanghaiChina
| | - Qin Pan
- Department of GastroenterologyXinhua Hospital, Shanghai Jiao Tong University School of MedicineShanghaiChina
| | - Jian Gao Fan
- Department of GastroenterologyXinhua Hospital, Shanghai Jiao Tong University School of MedicineShanghaiChina
- Shanghai Key Laboratory of Children's Digestion and NutritionShanghaiChina
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Qureshi K, Neuschwander-Tetri BA. The molecular basis for current targets of NASH therapies. Expert Opin Investig Drugs 2019; 29:151-161. [PMID: 31847612 DOI: 10.1080/13543784.2020.1703949] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Introduction: Nonalcoholic steatohepatitis (NASH) is a leading cause of liver disease in children and adults, a major contributor to health-care expenditures, and now a leading reason for liver transplantation. Adopting lifestyle modifications with regular exercise and a focus on healthy eating habits is the primary recommendation. However, patients are often unable to achieve and sustain such changes for a variety of social, physical, psychological and genetic reasons. Thus, treatments that can prevent and reverse NASH and its associated fibrosis are a major focus of current drug development.Areas covered: This review covers the current understanding of lipotoxic liver injury in the pathogenesis of NASH and how lifestyle modification and the spectrum of drugs currently in clinical trials address the many pathways leading to the phenotype of NASH.Expert opinion: Contrary to the frequently expressed nihilistic view of our understanding of NASH and disappointment with clinical trial results, much is known about the pathogenesis of NASH and there is much reason to be optimistic that effective therapies will be identified in the next 5-10 years. Achieving this will require continued refinement of clinical trial endpoints, continued engagement of trial sponsors and regulatory authorities, and continued participation of dedicated patients in clinical trials.
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Affiliation(s)
- Kamran Qureshi
- Division of Gastroenterology and Hepatology, Saint Louis University, St. Louis, MO, USA
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Oleic Acid Protects against Hepatic Ischemia and Reperfusion Injury in Mice by Inhibiting AKT/mTOR Pathways. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:4842592. [PMID: 31915509 PMCID: PMC6930725 DOI: 10.1155/2019/4842592] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Revised: 10/22/2019] [Accepted: 11/18/2019] [Indexed: 01/19/2023]
Abstract
Hepatic ischemia-reperfusion (I/R) injury is a serious complication in patients who have undergone hepatic surgery such as orthotopic liver transplantation and partial hepatectomy. Recently, a new cytoprotective agent, ursodeoxycholyl lysophosphatidylethanolamide (UDCA-LPE), was reported to protect against hepatic I/R injury. However, the protective mechanism of UDCA-LPE is not fully understood. Therefore, we conducted this study to explore its underlying mechanism. We used liquid chromatography-tandem mass spectrometry (LC-MS/MS) to analyze the liver lipid metabolism changes in mice during I/R. KEGG enrichment indicated that UDCA-LPE is likely to exert its protective role by regulating fatty acid (FA) metabolism. Further analysis found that UDCA-LPE significantly increased the ratio of oleic acid (OA) to palmitic acid (PA). We found that mice pretreated with OA improved tolerance to hepatic I/R injury. In addition, the phosphorylation level of AKT was markedly upregulated during oxidative stress to promote p65 nuclear translocation, triggering an inflammatory response that exacerbated cell damage and OA treatment significantly inhibited this process. Notably, OA was found to inhibit H2O2-induced oxidative stress, inflammation, and cell death in HepG2 cells. Furthermore, we found that OA supplementation to the medium did not result in a significant increase in intracellular OA, but marked increase in the ratio of OA to PA, which may be an important mechanism for the inflammatory response induced by oxidative stress during I/R. Finally, we demonstrated that OA increased the level of autophagy in HepG2 cells, which may be one of the protective mechanisms against oxidative stress. Collectively, this study revealed that FA metabolism functionally determines the oxidative stress-related inflammation caused by hepatic I/R. We hypothesize that OA treatment may be a promising strategy for preventing and treating I/R-induced liver damage.
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Stremmel W, Staffer S, Fricker G, Weiskirchen R. The Bile Acid-Phospholipid Conjugate Ursodeoxycholyl-Lysophosphatidylethanolamide (UDCA-LPE) Disintegrates the Lipid Backbone of Raft Plasma Membrane Domains by the Removal of the Membrane Phospholipase A2. Int J Mol Sci 2019; 20:ijms20225631. [PMID: 31717968 PMCID: PMC6888454 DOI: 10.3390/ijms20225631] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Revised: 10/28/2019] [Accepted: 11/06/2019] [Indexed: 01/07/2023] Open
Abstract
The bile acid-phospholipid conjugate ursodeoxycholyl-lysophosphatidylethanolamide (UDCA-LPE) was shown to have anti-inflammatory, antisteatotic, and antifibrotic properties, rendering it as a drug targeting non-alcoholic steatohepatitis (NASH). On a molecular level, it disrupted the heterotetrameric fatty acid uptake complex localized in detergent-resistant membrane domains of the plasma membrane (DRM-PM). However, its mode of action was unclear. Methodologically, UDCA-LPE was incubated with the liver tumor cell line HepG2 as well as their isolated DRM-PM and all other cellular membranes (non-DRM). The membrane cholesterol and phospholipids were quantified as well as the DRM-PM protein composition by Western blotting. The results show a loss of DRM-PM by UDCA-LPE (50 µM) with a 63.13 ± 7.14% reduction of phospholipids and an 81.94 ± 8.30% reduction of cholesterol in relation to mg total protein. The ratio of phospholipids to cholesterol changed from 2:1 to 4:1, resembling those of non-DRM fractions. Among the members of the fatty acid uptake complex, the calcium-independent membrane phospholipase A2 (iPLA2β) abandoned DRM-PM most rapidly. As a consequence, the other members of this transport system disappeared as well as the DRM-PM anchored fibrosis regulating proteins integrin β-1 and lysophospholipid receptor 1 (LPAR-1). It is concluded that UDCA-LPE executes its action by iPLA2β removal from DRM-PM and consequent dissolution of the raft lipid platform.
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Affiliation(s)
- Wolfgang Stremmel
- Institute of Pharmacy and Molecular Biotechnology, University of Heidelberg, 69120 Heidelberg, Germany;
- Correspondence: ; Tel.: +49-152-34349907
| | - Simone Staffer
- Department of Internal Medicine IV, University Hospital of Heidelberg, 69120 Heidelberg, Germany;
| | - Gert Fricker
- Institute of Pharmacy and Molecular Biotechnology, University of Heidelberg, 69120 Heidelberg, Germany;
| | - Ralf Weiskirchen
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry, RWTH University Hospital Aachen, 52074 Aachen, Germany;
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15
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Mato JM, Alonso C, Noureddin M, Lu SC. Biomarkers and subtypes of deranged lipid metabolism in non-alcoholic fatty liver disease. World J Gastroenterol 2019; 25:3009-3020. [PMID: 31293337 PMCID: PMC6603806 DOI: 10.3748/wjg.v25.i24.3009] [Citation(s) in RCA: 135] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Revised: 05/06/2019] [Accepted: 05/18/2019] [Indexed: 02/06/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a heterogeneous and complex disease that is imprecisely diagnosed by liver biopsy. NAFLD covers a spectrum that ranges from simple steatosis, nonalcoholic steatohepatitis (NASH) with varying degrees of fibrosis, to cirrhosis, which is a major risk factor for hepatocellular carcinoma. Lifestyle and eating habit changes during the last century have made NAFLD the most common liver disease linked to obesity, type 2 diabetes mellitus and dyslipidemia, with a global prevalence of 25%. NAFLD arises when the uptake of fatty acids (FA) and triglycerides (TG) from circulation and de novo lipogenesis saturate the rate of FA β-oxidation and very-low density lipoprotein (VLDL)-TG export. Deranged lipid metabolism is also associated with NAFLD progression from steatosis to NASH, and therefore, alterations in liver and serum lipidomic signatures are good indicators of the disease’s development and progression. This review focuses on the importance of the classification of NAFLD patients into different subtypes, corresponding to the main alteration(s) in the major pathways that regulate FA homeostasis leading, in each case, to the initiation and progression of NASH. This concept also supports the targeted intervention as a key approach to maximize therapeutic efficacy and opens the door to the development of precise NASH treatments.
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Affiliation(s)
- José M Mato
- CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Technology Park of Bizkaia, Derio 48160, Bizkaia, Spain
| | - Cristina Alonso
- OWL Metabolomics, Technology Park of Bizkaia, Derio 48160, Bizkaia, Spain
| | - Mazen Noureddin
- Division of Digestive and Liver Diseases, Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States
| | - Shelly C Lu
- Division of Digestive and Liver Diseases, Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States
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16
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Zhu X, Gan-Schreier H, Otto AC, Cheng Y, Staffer S, Tuma-Kellner S, Ganzha A, Liebisch G, Chamulitrat W. iPla2β deficiency in mice fed with MCD diet does not correct the defect of phospholipid remodeling but attenuates hepatocellular injury via an inhibition of lipid uptake genes. Biochim Biophys Acta Mol Cell Biol Lipids 2019; 1864:677-687. [PMID: 30735854 DOI: 10.1016/j.bbalip.2019.02.003] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2018] [Revised: 02/01/2019] [Accepted: 02/03/2019] [Indexed: 12/19/2022]
Abstract
Group VIA calcium-independent phospholipase A2 (iPla2β) is among modifier genes of non-alcoholic fatty liver disease which leads to non-alcoholic steatohepatitis (NASH). Consistently, iPla2β deletion protects hepatic steatosis and obesity in genetic ob/ob and obese mice chronically fed with high-fat diet by replenishing the loss of hepatic phospholipids (PL). As mouse feeding with methionine- and choline-deficient (MCD) diet is a model of lean NASH, we tested whether iPla2β-null mice could still be protected since PL syntheses are disturbed. MCD-diet feeding of female wild-type for 5 weeks induced hepatic steatosis with a severe reduction of body and visceral fat weights concomitant with a decrease of hepatic phosphatidylcholine. These parameters were not altered in MCD-fed iPla2β-null mice. However, iPla2β deficiency attenuated MCD-induced elevation of serum transaminase activities and hepatic expression of fatty-acid translocase Cd36, fatty-acid binding protein-4, peroxisome-proliferator activated receptorγ, and HDL-uptake scavenger receptor B type 1. The reduction of lipid uptake genes was consistent with a decrease of hepatic esterified and unesterified fatty acids and cholesterol esters. On the contrary, iPla2β deficiency under MCD did not have any effects on inflammasomes and pro-inflammatory markers but exacerbated hepatic expression of myofibroblast α-smooth muscle actin and vimentin. Thus, without any rescue of PL loss, iPla2β inactivation attenuated hepatocellular injury in MCD-induced NASH with a novel mechanism of lipid uptake inhibition. Taken together, we have shown that iPla2β mediates hepatic steatosis and lipotoxicity in hepatocytes in both obese and lean NASH, but elicits exacerbated liver fibrosis in lean NASH likely by affecting other cell types.
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Affiliation(s)
- Xingya Zhu
- Department of Internal Medicine IV, University of Heidelberg Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany
| | - Hongying Gan-Schreier
- Department of Internal Medicine IV, University of Heidelberg Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany
| | - Ann-Christin Otto
- Department of Internal Medicine IV, University of Heidelberg Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany
| | - Yuting Cheng
- Department of Internal Medicine IV, University of Heidelberg Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany
| | - Simone Staffer
- Department of Internal Medicine IV, University of Heidelberg Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany
| | - Sabine Tuma-Kellner
- Department of Internal Medicine IV, University of Heidelberg Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany
| | - Alexandra Ganzha
- Institute of Clinical Chemistry and Laboratory Medicine, University of Regensburg, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany
| | - Gerhard Liebisch
- Institute of Clinical Chemistry and Laboratory Medicine, University of Regensburg, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany
| | - Walee Chamulitrat
- Department of Internal Medicine IV, University of Heidelberg Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
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17
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Stremmel W, Staffer S, Gehrke S. The Detergent Effect of Mesalazine Interferes with Phosphatidylcholine Binding to Mucin 2. Inflamm Intest Dis 2018; 3:107-115. [PMID: 30820432 DOI: 10.1159/000493347] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2018] [Accepted: 08/29/2018] [Indexed: 12/14/2022] Open
Abstract
Objectives Therapeutically applied delayed-release phosphatidylcholine (PC) revealed mucosa protection and clinical improvement of ulcerative colitis. However, a recent trial with simultaneous application of delayed-release PC and mesalazine showed lack of efficacy. It is hypothesized that mesalazine acts as detergent to prohibit PC integration into mucus as target compartment, thus preventing topical mucus protection. Methods In vitro PC-binding studies with mucin 2 and intestinally differentiated CaCo2 cells as well as outcome analysis of a therapeutic trial with delayed-release PC and additional mesalazine. Results Choline-containing phospholipids, in particular PC, bind to mucin 2 as main scaffold protein of intestinal mucus to establish a hydrophobic barrier towards microbiota in the intestinal lumen. PC also binds to the apical surface of polarized CaCo2 cells with membrane-anchored mucin 3. Mesalazine removes mucin-bound PC and, thus, reduces transepithelial resistance. A post hoc analysis of patients from a previous multicenter phase IIB trial with delayed-release PC revealed that those without mesalazine showed a PC dose-dependent outcome with regard to achievement of partial and complete remission (p < 0.05 for 1.6 and 3.2 g PC daily) whereas those treated simultaneously with mesalazine showed no PC dose dependency. Conclusion Mesalazine solubilizes PC and, thus, prevents the protective action of therapeutically applied delayed-release PC within mucus.
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Affiliation(s)
- Wolfgang Stremmel
- Department of Gastroenterology and Infectious Diseases, University Hospital of Heidelberg, Heidelberg, Germany
| | - Simone Staffer
- Department of Gastroenterology and Infectious Diseases, University Hospital of Heidelberg, Heidelberg, Germany
| | - Sven Gehrke
- Medical Center Baden-Baden, Baden-Baden, Germany
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18
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Musso G, Cassader M, Paschetta E, Gambino R. Bioactive Lipid Species and Metabolic Pathways in Progression and Resolution of Nonalcoholic Steatohepatitis. Gastroenterology 2018; 155:282-302.e8. [PMID: 29906416 DOI: 10.1053/j.gastro.2018.06.031] [Citation(s) in RCA: 236] [Impact Index Per Article: 33.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2017] [Revised: 05/30/2018] [Accepted: 06/01/2018] [Indexed: 02/06/2023]
Abstract
The prevalence of nonalcoholic steatohepatitis (NASH) is increasing worldwide, yet there are no effective treatments. A decade has passed since the initial lipidomics analyses of liver tissues from patients with nonalcoholic fatty liver disease. We have learned that liver cells from patients with NASH have an abnormal lipid composition and that the accumulation of lipids leads to organelle dysfunction, cell injury and death, and chronic inflammation, called lipotoxicity. We review the lipid species and metabolic pathways that contribute to the pathogenesis of NASH and potential therapeutic targets, including enzymes involved in fatty acid and triglyceride synthesis, bioactive sphingolipids and polyunsaturated-derived eicosanoids, and specialized pro-resolving lipid mediators. We discuss the concept that NASH is a disease that can resolve and the roles of lipid molecules in the resolution of inflammation and regression of fibrosis.
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Affiliation(s)
| | - Maurizio Cassader
- Department of Medical Sciences, San Giovanni Battista Hospital, University of Turin, Turin, Italy
| | | | - Roberto Gambino
- Department of Medical Sciences, San Giovanni Battista Hospital, University of Turin, Turin, Italy
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19
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Mendez-Sanchez N, Cruz-Ramon VC, Ramirez-Perez OL, Hwang JP, Barranco-Fragoso B, Cordova-Gallardo J. New Aspects of Lipotoxicity in Nonalcoholic Steatohepatitis. Int J Mol Sci 2018; 19:E2034. [PMID: 30011790 PMCID: PMC6073816 DOI: 10.3390/ijms19072034] [Citation(s) in RCA: 122] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2018] [Revised: 07/09/2018] [Accepted: 07/11/2018] [Indexed: 02/08/2023] Open
Abstract
NASH is becoming increasingly common worldwide because of the growing global prevalence of obesity and consequently NAFLD. Unfortunately, the mechanism of progression of NAFLD to NASH and then cirrhosis is not completely understood. Several factors, including insulin resistance, inflammation, oxidative stress, lipotoxicity, and bile acid (BA) toxicity, have been reported to be associated with NASH progression. The release of fatty acids from dysfunctional and insulin-resistant adipocytes results in lipotoxicity, which is caused by the ectopic accumulation of triglyceride-derived toxic metabolites and the subsequent activation of inflammatory pathways, cellular dysfunction, and lipoapoptosis. Adipose tissue (AT), especially visceral AT, comprises multiple cell populations that produce adipokines and insulin-like growth factor, plus macrophages and other immune cells that stimulate the development of lipotoxic liver disease. These biomolecules have been recently linked with many digestive diseases and gastrointestinal malignancies such as hepatocellular carcinoma. This made us question what role lipotoxicity has in the natural history of liver fibrosis. Therefore, this review focuses on the close relationship between AT and NASH. A good comprehension of the pathways that are related to dysregulated AT, metabolic dysfunction, and hepatic lipotoxicity will result in the development of prevention strategies and promising therapeutics for patients with NASH.
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Affiliation(s)
| | | | | | - Jessica P Hwang
- Department of General Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
| | - Beatriz Barranco-Fragoso
- Department of Gastroenterology, National Medical Center "20 Noviembre", 03229 Mexico City, Mexico.
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20
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Siebers K, Fink B, Zakrzewicz A, Agné A, Richter K, Konzok S, Hecker A, Zukunft S, Küllmar M, Klein J, McIntosh JM, Timm T, Sewald K, Padberg W, Aggarwal N, Chamulitrat W, Santoso S, Xia W, Janciauskiene S, Grau V. Alpha-1 Antitrypsin Inhibits ATP-Mediated Release of Interleukin-1β via CD36 and Nicotinic Acetylcholine Receptors. Front Immunol 2018; 9:877. [PMID: 29922281 PMCID: PMC5996888 DOI: 10.3389/fimmu.2018.00877] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2018] [Accepted: 04/09/2018] [Indexed: 12/30/2022] Open
Abstract
While interleukin (IL)-1β is a potent pro-inflammatory cytokine involved in host defense, high levels can cause life-threatening sterile inflammation including systemic inflammatory response syndrome. Hence, the control of IL-1β secretion is of outstanding biomedical importance. In response to a first inflammatory stimulus such as lipopolysaccharide, pro-IL-1β is synthesized as a cytoplasmic inactive pro-form. Extracellular ATP originating from injured cells is a prototypical second signal for inflammasome-dependent maturation and release of IL-1β. The human anti-protease alpha-1 antitrypsin (AAT) and IL-1β regulate each other via mechanisms that are only partially understood. Here, we demonstrate that physiological concentrations of AAT efficiently inhibit ATP-induced release of IL-1β from primary human blood mononuclear cells, monocytic U937 cells, and rat lung tissue, whereas ATP-independent IL-1β release is not impaired. Both, native and oxidized AAT are active, suggesting that the inhibition of IL-1β release is independent of the anti-elastase activity of AAT. Signaling of AAT in monocytic cells involves the lipid scavenger receptor CD36, calcium-independent phospholipase A2β, and the release of a small soluble mediator. This mediator leads to the activation of nicotinic acetylcholine receptors, which efficiently inhibit ATP-induced P2X7 receptor activation and inflammasome assembly. We suggest that AAT controls ATP-induced IL-1β release from human mononuclear blood cells by a novel triple-membrane-passing signaling pathway. This pathway may have clinical implications for the prevention of sterile pulmonary and systemic inflammation.
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Affiliation(s)
- Kathrin Siebers
- Laboratory of Experimental Surgery, Department of General and Thoracic Surgery, Justus Liebig University Giessen, German Centre for Lung Research, Giessen, Germany
| | - Bijan Fink
- Laboratory of Experimental Surgery, Department of General and Thoracic Surgery, Justus Liebig University Giessen, German Centre for Lung Research, Giessen, Germany
| | - Anna Zakrzewicz
- Laboratory of Experimental Surgery, Department of General and Thoracic Surgery, Justus Liebig University Giessen, German Centre for Lung Research, Giessen, Germany
| | - Alisa Agné
- Laboratory of Experimental Surgery, Department of General and Thoracic Surgery, Justus Liebig University Giessen, German Centre for Lung Research, Giessen, Germany
| | - Katrin Richter
- Laboratory of Experimental Surgery, Department of General and Thoracic Surgery, Justus Liebig University Giessen, German Centre for Lung Research, Giessen, Germany
| | - Sebastian Konzok
- Fraunhofer Institute for Toxicology and Experimental Medicine, German Centre for Lung Research, Hannover, Germany
| | - Andreas Hecker
- Laboratory of Experimental Surgery, Department of General and Thoracic Surgery, Justus Liebig University Giessen, German Centre for Lung Research, Giessen, Germany
| | - Sven Zukunft
- Institute of Vascular Signalling, Centre for Molecular Medicine, Goethe University, Frankfurt, Germany
| | - Mira Küllmar
- Laboratory of Experimental Surgery, Department of General and Thoracic Surgery, Justus Liebig University Giessen, German Centre for Lung Research, Giessen, Germany
| | - Jochen Klein
- Department of Pharmacology, Goethe University College of Pharmacy, Frankfurt, Germany
| | - J Michael McIntosh
- Department of Biology, University of Utah, Salt Lake City, UT, United States.,George E. Wahlen Veterans Affairs Medical Center, Salt Lake City, UT, United States.,Department of Psychiatry, University of Utah, Salt Lake City, UT, United States
| | - Thomas Timm
- Protein Analytics, Institute of Biochemistry, Justus Liebig University Giessen, Giessen, Germany
| | - Katherina Sewald
- Fraunhofer Institute for Toxicology and Experimental Medicine, German Centre for Lung Research, Hannover, Germany
| | - Winfried Padberg
- Laboratory of Experimental Surgery, Department of General and Thoracic Surgery, Justus Liebig University Giessen, German Centre for Lung Research, Giessen, Germany
| | - Nupur Aggarwal
- Department of Respiratory Medicine, Hannover Medical School, German Centre for Lung Research, Hannover, Germany
| | - Walee Chamulitrat
- Department of Internal Medicine IV, University Heidelberg Hospital, Heidelberg, Germany
| | - Sentot Santoso
- Institute for Clinical Immunology and Transfusion Medicine, Justus Liebig University Giessen, Giessen, Germany
| | - Wendy Xia
- Institute of Blood Transfusion, Guangzhou Blood Centre, Guangzhou, China
| | - Sabina Janciauskiene
- Department of Respiratory Medicine, Hannover Medical School, German Centre for Lung Research, Hannover, Germany
| | - Veronika Grau
- Laboratory of Experimental Surgery, Department of General and Thoracic Surgery, Justus Liebig University Giessen, German Centre for Lung Research, Giessen, Germany
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21
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Stremmel W, Staffer S, Stuhrmann N, Gan-Schreier H, Gauss A, Burger N, Hornuss D. Phospholipase A 2 of Microbiota as Pathogenetic Determinant to Induce Inflammatory States in Ulcerative Colitis: Therapeutic Implications of Phospholipase A 2 Inhibitors. Inflamm Intest Dis 2018; 2:180-187. [PMID: 29922677 DOI: 10.1159/000486858] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2017] [Accepted: 01/12/2018] [Indexed: 12/17/2022] Open
Abstract
Background Attack by commensal microbiota is one component of induction of inflammatory episodes in ulcerative colitis (UC). In UC, the mucus layer is intrinsically devoid of phosphatidylcholine (PC) resulting in low hydrophobicity which facilitates bacterial invasion. Colonic ectophospholipase-carrying bacterial strains are likely candidates to further thinning the PC mucus barrier and to precipitate inflammatory episodes. Objective To evaluate the effect of phospholipase A2 (PLA2) inhibitors on inflammation in a genetic UC mouse model. Methods As PLA2 inhibitor, we applied the bile acid-phospholipid conjugate ursodeoxycholate-lysophosphatidylethanolamide (UDCA-LPE) or as control 5% Tween 80 by oral gavage to intestine-specific kindlin 2 knockout mice. Results Luminal UDCA-LPE reduced the PLA2 activity in stool by 36 ± 8%. Concomitantly no inflammatory phenotype was observed when compared to kindlin 2(-/-) mice not treated with UDCA-LPE. The improvement was documented in regard to stool consistency, calprotectin levels in stool, and macroscopic/endoscopic as well as histologic features of the mucosa. The pattern of colonic microbiota distribution obtained in the UC phenotype mice was reversed by UDCA-LPE to the control mice pattern. Conclusion The inhibition of the bacterial ectophospholipase A2 activity improves mucosal inflammation in a genetic mouse model of UC. It is assumed that the remaining mucus PC shield is better preserved when luminal PLA2 is suppressed.
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Affiliation(s)
- Wolfgang Stremmel
- Department of Internal Medicine IV, University Clinics of Heidelberg, Heidelberg, Germany
| | - Simone Staffer
- Department of Internal Medicine IV, University Clinics of Heidelberg, Heidelberg, Germany
| | - Nicole Stuhrmann
- Department of Internal Medicine IV, University Clinics of Heidelberg, Heidelberg, Germany
| | - Hongying Gan-Schreier
- Department of Internal Medicine IV, University Clinics of Heidelberg, Heidelberg, Germany
| | - Annika Gauss
- Department of Internal Medicine IV, University Clinics of Heidelberg, Heidelberg, Germany
| | - Nina Burger
- Department of Internal Medicine IV, University Clinics of Heidelberg, Heidelberg, Germany
| | - Daniel Hornuss
- Department of Internal Medicine IV, University Clinics of Heidelberg, Heidelberg, Germany
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22
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Malley KR, Koroleva O, Miller I, Sanishvili R, Jenkins CM, Gross RW, Korolev S. The structure of iPLA 2β reveals dimeric active sites and suggests mechanisms of regulation and localization. Nat Commun 2018; 9:765. [PMID: 29472584 PMCID: PMC5823874 DOI: 10.1038/s41467-018-03193-0] [Citation(s) in RCA: 59] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2017] [Accepted: 01/26/2018] [Indexed: 11/17/2022] Open
Abstract
Calcium-independent phospholipase A2β (iPLA2β) regulates important physiological processes including inflammation, calcium homeostasis and apoptosis. It is genetically linked to neurodegenerative disorders including Parkinson’s disease. Despite its known enzymatic activity, the mechanisms underlying iPLA2β-induced pathologic phenotypes remain poorly understood. Here, we present a crystal structure of iPLA2β that significantly revises existing mechanistic models. The catalytic domains form a tight dimer. They are surrounded by ankyrin repeat domains that adopt an outwardly flared orientation, poised to interact with membrane proteins. The closely integrated active sites are positioned for cooperative activation and internal transacylation. The structure and additional solution studies suggest that both catalytic domains can be bound and allosterically inhibited by a single calmodulin. These features suggest mechanisms of iPLA2β cellular localization and activity regulation, providing a basis for inhibitor development. Furthermore, the structure provides a framework to investigate the role of neurodegenerative mutations and the function of iPLA2β in the brain. Calcium-independent phospholipase A2β (iPLA2β) is involved in many physiological and pathological processes but the underlying mechanisms are largely unknown. Here, the authors present the structure of dimeric iPLA2β, providing insights into the regulation of its activity and cellular localization.
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Affiliation(s)
- Konstantin R Malley
- Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO, 63104, USA
| | - Olga Koroleva
- Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO, 63104, USA
| | - Ian Miller
- Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO, 63104, USA
| | - Ruslan Sanishvili
- GM/CA@APS, Advanced Photon Source, Argonne National Laboratory, Argonne, IL, 60439, USA
| | - Christopher M Jenkins
- Division of Bioorganic Chemistry and Molecular Pharmacology, Department of Medicine, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8020, Saint Louis, MO, 63110, USA
| | - Richard W Gross
- Division of Bioorganic Chemistry and Molecular Pharmacology, Department of Medicine, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8020, Saint Louis, MO, 63110, USA.,Department of Developmental Biology, Washington University School of Medicine, Saint Louis, MO, 63110, USA.,Department of Medicine, Center for Cardiovascular Research, Washington University School of Medicine, Saint Louis, MO, 63110, USA.,Department of Chemistry, Washington University, Saint Louis, MO, 63130, USA
| | - Sergey Korolev
- Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO, 63104, USA.
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23
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Abstract
Triglyceride molecules represent the major form of storage and transport of fatty acids within cells and in the plasma. The liver is the central organ for fatty acid metabolism. Fatty acids accrue in liver by hepatocellular uptake from the plasma and by de novo biosynthesis. Fatty acids are eliminated by oxidation within the cell or by secretion into the plasma within triglyceride-rich very low-density lipoproteins. Notwithstanding high fluxes through these pathways, under normal circumstances the liver stores only small amounts of fatty acids as triglycerides. In the setting of overnutrition and obesity, hepatic fatty acid metabolism is altered, commonly leading to the accumulation of triglycerides within hepatocytes, and to a clinical condition known as nonalcoholic fatty liver disease (NAFLD). In this review, we describe the current understanding of fatty acid and triglyceride metabolism in the liver and its regulation in health and disease, identifying potential directions for future research. Advances in understanding the molecular mechanisms underlying the hepatic fat accumulation are critical to the development of targeted therapies for NAFLD. © 2018 American Physiological Society. Compr Physiol 8:1-22, 2018.
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Affiliation(s)
- Michele Alves-Bezerra
- Joan & Sanford I. Weill Department of Medicine, Weill Cornell Medical College, New York, USA
| | - David E Cohen
- Joan & Sanford I. Weill Department of Medicine, Weill Cornell Medical College, New York, USA
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24
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Stremmel W, Staffer S, Schneider MJ, Gan-Schreier H, Wannhoff A, Stuhrmann N, Gauss A, Wolburg H, Mahringer A, Swidsinski A, Efferth T. Genetic Mouse Models with Intestinal-Specific Tight Junction Deletion Resemble an Ulcerative Colitis Phenotype. J Crohns Colitis 2017; 11:1247-1257. [PMID: 28575164 PMCID: PMC5881657 DOI: 10.1093/ecco-jcc/jjx075] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2017] [Accepted: 05/23/2017] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIMS A key pathogenetic feature of ulcerative colitis [UC] is an intrinsic low mucus phosphatidylcholine[PC] content. Recently, a paracellular transport for PC across tight junctions[TJs] was described, suggesting TJ disturbance as a cause of diminished luminal PC transport. Therefore, we aimed to generate mutant mice with TJ deletion to evaluate whether a UC phenotype developed. METHODS CL57BL/6 control wild-type mice were compared to mutant mice with tamoxifen-induced villin-Cre-dependent intestinal deletion of kindlin 1 and 2. RESULTS Electron microscopy of mucosal biopsies obtained from both mutants before overt inflammation following only 2 days of tamoxifen exposure revealed a defective TJ morphology with extended paracellular space and, by light microscopy, expanded mucosal crypt lumina. PC secretion into mucus was reduced by >65% and the mucus PC content dropped by >50%, causing a >50 % decrease of mucus hydrophobicity in both mutants. Consequently, the microbiota was able to penetrate the submucosa. After 3 days of tamoxifen exposure, intestinal inflammation was present in both mutants, with loose bloody stools as well as macroscopic and histological features of colitis. Oral PC supplementation was able to suppress inflammation. By analogy, colonic biopsies obtained from patients with UC in remission also showed a defective epithelium with widened intercellular clefts, and enlarged crypt luminal diameters with functionally impaired luminal PC secretion. CONCLUSIONS Genetic mouse models with intestinal deletion of kindlin 1 and 2 resulted in TJ deletion and revealed pathophysiological features of impaired PC secretion to the mucus leading to mucosal inflammation compatible with human UC.
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Affiliation(s)
- Wolfgang Stremmel
- Department of Internal Medicine IV, University Clinics of Heidelberg, Heidelberg, Germany,Corresponding author: Wolfgang Stremmel, MD, PhD, Professor of Medicine, University Clinics of Heidelberg, Department of Internal Medicine IV, 69120 Heidelberg, Germany. Tel: +49 6221 56 8700;
| | - Simone Staffer
- Department of Internal Medicine IV, University Clinics of Heidelberg, Heidelberg, Germany
| | | | - Hongying Gan-Schreier
- Department of Internal Medicine IV, University Clinics of Heidelberg, Heidelberg, Germany
| | - Andreas Wannhoff
- Department of Internal Medicine IV, University Clinics of Heidelberg, Heidelberg, Germany
| | - Nicole Stuhrmann
- Department of Internal Medicine IV, University Clinics of Heidelberg, Heidelberg, Germany
| | - Annika Gauss
- Department of Internal Medicine IV, University Clinics of Heidelberg, Heidelberg, Germany
| | - Hartwig Wolburg
- Department of Pathology and Neuropathology, University Medical School of Tübingen, Tübingen, Germany
| | - Anne Mahringer
- Institute of Pharmacy and Molecular Biotechnology, Ruprecht-Karls-University of Heidelberg, Heidelberg, Germany
| | - Alexander Swidsinski
- Department of Gastroenterology, University Hospital Charité of Berlin, 10115 Berlin, Germany
| | - Thomas Efferth
- Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Mainz, Germany
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25
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Stremmel W, Staffer S, Wannhoff A, Pathil A. The overall fatty acid absorption controlled by basolateral chylomicron excretion under regulation of p-JNK1. Biochim Biophys Acta Mol Cell Biol Lipids 2017; 1862:917-928. [PMID: 28602806 DOI: 10.1016/j.bbalip.2017.05.013] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2017] [Revised: 05/05/2017] [Accepted: 05/17/2017] [Indexed: 11/26/2022]
Abstract
Suppression of fatty acid absorption is one goal to fight obesity. However, the responsible molecular mechanism is poorly understood. Aim of the present study was the search for the key regulator of the overall fatty acid absorption mechanism and its pharmaceutical modulation. As experimental tool we employed the polarized human intestinal tumor derived cell line CaCo2. Here we showed that influx of fatty acids is mediated by an apical heterotetrameric plasma membrane protein complex of which the calcium-independent membrane phospholipase A2 (iPLA2ß) is one constituent. The newly synthesized bile acid-phospholipid conjugate ursodeoxycholate-lysophosphatidylethanolamide (UDCA-LPE) blocked iPLA2ß, which structurally disrupted the fatty acid-uptake complex. Furthermore, the inhibition of iPLA2ß lead to reduction of cytosolic lysophosphatidylcholine (LPC) production which suppressed p-JNK1, as a central regulator of metabolism. In a concerted action low p-JNK1 levels prohibited synthesis of the members of the fatty acid uptake complex as well as of apolipoprotein B and the connected members of the basolateral vesicular chylomicron excretion machinery, thereby inhibiting cellular lipid excretion. The basolateral chylomicron release was shown to determine the overall fatty acid-absorption capacity as rate limiting step, whereas apical uptake replenishes the cellular stores, enabling continuous transcellular movement of fatty acids. In conclusion, the UDCA-LPE mediated inhibition of p-JNK1 represents a powerful tool to control intestinal absorption of fatty acids and, thus may be employed as a drug to treat obesity.
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Affiliation(s)
- Wolfgang Stremmel
- Department of Internal Medicine, University Hospital of Heidelberg, INF 410, 69120 Heidelberg, Germany.
| | - Simone Staffer
- Department of Internal Medicine, University Hospital of Heidelberg, INF 410, 69120 Heidelberg, Germany
| | - Andreas Wannhoff
- Department of Internal Medicine, University Hospital of Heidelberg, INF 410, 69120 Heidelberg, Germany
| | - Anita Pathil
- Department of Internal Medicine, University Hospital of Heidelberg, INF 410, 69120 Heidelberg, Germany
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26
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Caveolin-1 Function in Liver Physiology and Disease. Trends Mol Med 2016; 22:889-904. [DOI: 10.1016/j.molmed.2016.08.007] [Citation(s) in RCA: 56] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2016] [Revised: 08/14/2016] [Accepted: 08/17/2016] [Indexed: 12/18/2022]
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27
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Hirsova P, Ibrabim SH, Gores GJ, Malhi H. Lipotoxic lethal and sublethal stress signaling in hepatocytes: relevance to NASH pathogenesis. J Lipid Res 2016; 57:1758-1770. [PMID: 27049024 PMCID: PMC5036373 DOI: 10.1194/jlr.r066357] [Citation(s) in RCA: 191] [Impact Index Per Article: 21.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2016] [Revised: 04/05/2016] [Indexed: 12/12/2022] Open
Abstract
The accumulation of lipids is a histologic and biochemical hallmark of obesity-associated nonalcoholic fatty liver disease (NAFLD). A subset of NALFD patients develops progressive liver disease, termed nonalcoholic steatohepatitis, which is characterized by hepatocellular apoptosis and innate immune system-mediated inflammation. These responses are orchestrated by signaling pathways that can be activated by lipids, directly or indirectly. In this review, we discuss palmitate- and lysophosphatidylcholine (LPC)-induced upregulation of p53-upregulated modulator of apoptosis and cell-surface expression of the death receptor TNF-related apoptosis-inducing ligand receptor 2. Next, we review the activation of stress-induced kinases, mixed lineage kinase 3, and c-Jun N-terminal kinase, and the activation of endoplasmic reticulum stress response and its downstream proapoptotic effector, CAAT/enhancer binding homologous protein, by palmitate and LPC. Moreover, the activation of these stress signaling pathways is linked to the release of proinflammatory, proangiogenic, and profibrotic extracellular vesicles by stressed hepatocytes. This review discusses the signaling pathways induced by lethal and sublethal lipid overload that contribute to the pathogenesis of NAFLD.
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Affiliation(s)
- Petra Hirsova
- Divisions of Gastroenterology and Hepatology Mayo Clinic, Rochester, MN 55905
| | - Samar H Ibrabim
- Pediatric Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905
| | - Gregory J Gores
- Divisions of Gastroenterology and Hepatology Mayo Clinic, Rochester, MN 55905.
| | - Harmeet Malhi
- Divisions of Gastroenterology and Hepatology Mayo Clinic, Rochester, MN 55905.
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28
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Abstract
Nonalcoholic fatty liver disease (NAFLD) is characterized by fat deposition in hepatocytes, and a strong association with nutritional factors. Dietary fatty acids are classified according to their biochemical properties, which confer their bioactive roles. Monounsaturated fatty acids have a dual role in various human and murine models. In contrast, polyunsaturated fatty acids exhibit antiobesity, anti steatosic and anti-inflammatory effects. The combination of these forms of fatty acids—according to dietary type, daily intake and the proportion of n-6 to n-3 fats—can compromise hepatic lipid metabolism. A chemosensory rather than a nutritional role makes bioactive fatty acids possible biomarkers for NAFLD. Bioactive fatty acids provide health benefits through modification of fatty acid composition and modulating the activity of liver cells during liver fibrosis. More and better evidence is necessary to elucidate the role of bioactive fatty acids in nutritional and clinical treatment strategies for patients with NAFLD.
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29
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Mota M, Banini BA, Cazanave SC, Sanyal AJ. Molecular mechanisms of lipotoxicity and glucotoxicity in nonalcoholic fatty liver disease. Metabolism 2016; 65:1049-61. [PMID: 26997538 PMCID: PMC4931958 DOI: 10.1016/j.metabol.2016.02.014] [Citation(s) in RCA: 384] [Impact Index Per Article: 42.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2015] [Revised: 02/05/2016] [Accepted: 02/23/2016] [Indexed: 12/21/2022]
Abstract
The exposure of hepatocytes to high concentrations of lipids and carbohydrates and the ensuing hepatocellular injury are termed lipotoxicity and glucotoxicity, respectively. A common denominator is metabolic derangement, especially in regards to intracellular energy homeostasis, which is brought on by glucose intolerance and insulin resistance in tissues. In this review, we highlight the lipids and carbohydrates that provoke hepatocyte injury and the mechanisms involved in lipotoxicity and glucotoxicity, including endoplasmic reticulum stress, oxidative stress and mitochondrial impairment. Through upregulation of proteins involved in various pathways including PKR-like ER kinase (PERK), CCAAT/enhancer-binding homologous protein (CHOP), c-Jun NH2-terminal kinase-1 (JNK), Bcl-2 interacting mediator (BIM), p53 upregulated modulator of apoptosis (PUMA), and eventually caspases, hepatocytes in lipotoxic states ultimately undergo apoptosis. The protective role of certain lipids and possible targets for pharmacological therapy are explored. Finally, we discuss the role of high fructose and glucose diets in contributing to organelle impairment and poor glucose transport mechanisms, which perpetuate hyperglycemia and hyperlipidemia by shunting of excess carbohydrates into lipogenesis.
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Affiliation(s)
- Manoela Mota
- Department of Internal Medicine, Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.
| | - Bubu A Banini
- Department of Internal Medicine, Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University School of Medicine, Richmond, VA, USA
| | - Sophie C Cazanave
- Department of Internal Medicine, Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University School of Medicine, Richmond, VA, USA
| | - Arun J Sanyal
- Department of Internal Medicine, Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.
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30
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Abstract
Obesity and its major comorbidities, including type 2 diabetes mellitus, nonalcoholic fatty liver disease (NAFLD), obesity cardiomyopathy, and certain cancers, have caused life expectancy in the United States to decline in recent years. Obesity is the increased accumulation of triglycerides (TG), which are synthesized from glycerol and long-chain fatty acids (LCFA) throughout the body. LCFA enter adipocytes, hepatocytes, and cardiomyocytes via specific, facilitated transport processes. Metabolism of increased cellular TG content in obesity may lead to comorbidities such as NAFLD and cardiomyopathy. Better understanding of LCFA transport processes may lead to successful treatment of obesity and NAFLD.
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Affiliation(s)
- Paul D Berk
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia College of Physicians and Surgeons, Columbia University Medical Center, 650 West 168 Street, New York, NY 10032, USA; Division of Preventive Medicine, Department of Medicine, Columbia College of Physicians and Surgeons, Columbia University Medical Center, William Black Building, 650 West 168 Street, Room 1006, Box 57A, New York, NY 10032, USA.
| | - Elizabeth C Verna
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia College of Physicians and Surgeons, Columbia University Medical Center, 650 West 168 Street, New York, NY 10032, USA
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31
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Fabbrini E, Magkos F. Hepatic Steatosis as a Marker of Metabolic Dysfunction. Nutrients 2015; 7:4995-5019. [PMID: 26102213 PMCID: PMC4488828 DOI: 10.3390/nu7064995] [Citation(s) in RCA: 132] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2015] [Revised: 06/05/2015] [Accepted: 06/15/2015] [Indexed: 02/06/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the liver manifestation of the complex metabolic derangements associated with obesity. NAFLD is characterized by excessive deposition of fat in the liver (steatosis) and develops when hepatic fatty acid availability from plasma and de novo synthesis exceeds hepatic fatty acid disposal by oxidation and triglyceride export. Hepatic steatosis is therefore the biochemical result of an imbalance between complex pathways of lipid metabolism, and is associated with an array of adverse changes in glucose, fatty acid, and lipoprotein metabolism across all tissues of the body. Intrahepatic triglyceride (IHTG) content is therefore a very good marker (and in some cases may be the cause) of the presence and the degree of multiple-organ metabolic dysfunction. These metabolic abnormalities are likely responsible for many cardiometabolic risk factors associated with NAFLD, such as insulin resistance, type 2 diabetes mellitus, and dyslipidemia. Understanding the factors involved in the pathogenesis and pathophysiology of NAFLD will lead to a better understanding of the mechanisms responsible for the metabolic complications of obesity, and hopefully to the discovery of novel effective treatments for their reversal.
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Affiliation(s)
- Elisa Fabbrini
- Center for Human Nutrition and Atkins Center of Excellence in Obesity Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
| | - Faidon Magkos
- Center for Human Nutrition and Atkins Center of Excellence in Obesity Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
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