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Ivashkin VT, Drapkina OM, Maevskaya MV, Raikhelson KL, Okovityi SV, Zharkova MS, Grechishnikova VR, Abdulganieva DI, Alekseenko SA, Ardatskaya MD, Bakulin IG, Bakulina NV, Bogomolov PO, Breder VV, Vinnitskaya EV, Geyvandova NI, Golovanova EV, Grinevich VB, Doshchitsin VL, Dudinskaya EN, Ershova EV, Kodzoeva KB, Kozlova IV, Komshilova KA, Konev YV, Korochanskaya NV, Kotovskaya YV, Kravchuk YA, Loranskaya ID, Maev IV, Martynov AI, Mekhtiev SN, Mishina EE, Nadinskaia MY, Nikitin IG, Osipenko MF, Ostroumova OD, Pavlov CS, Pogosova NV, Radchenko VG, Roytberg GE, Saifutdinov RG, Samsonov AA, Seliverstov PV, Sitkin SI, Tarasova LV, Tarzimanova AI, Tkacheva ON, Tkachenko EI, Troshina EA, Turkina SV, Uspenskiy YP, Fominykh YA, Khlynova OV, Tsyganova YV, Shamkhalova MS, Sharkhun OO, Shestakova MV. Clinical Guidelines of the Russian Society for the Study of the Liver, Russian Gastroenterological Association, Russian Society for the Prevention of Non-Communicable Diseases, Russian Association of Endocrinologists, Russian Scientific Medical Society of Therapists, National Society of Preventive Cardiology, Russian Association of Gerontologists and Geriatricians on Non-Alcoholic Fatty Liver Disease. RUSSIAN JOURNAL OF GASTROENTEROLOGY, HEPATOLOGY, COLOPROCTOLOGY 2025; 35:94-152. [DOI: 10.22416/1382-4376-2025-35-1-94-152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/28/2025]
Abstract
Aim. The clinical guidelines are intended to provide information support for making decisions by gastroenterologists, general practitioners and internists that will improve the quality of medical care for patients with non-alcoholic fatty liver disease, taking into account the latest clinical data and principles of evidence-based medicine. Key points. Clinical guidelines contain information about current views on etiology, risk factors and pathogenesis of nonalcoholic fatty liver disease, peculiarities of its clinical course. Also given recommendations provide information on current methods of laboratory and instrumental diagnostics, invasive and non-invasive tools for nonalcoholic fatty liver disease and its clinical phenotypes assessment, approaches to its treatment, considering the presence of comorbidities, features of dispensary monitoring and prophylaxis. The information is illustrated with algorithms of differential diagnosis and physician's actions. In addition, there is information for the patient and criteria for assessing the quality of medical care. Conclusion. Awareness of specialists in the issues of diagnosis, treatment and follow-up of patients with nonalcoholic fatty liver disease contributes to the timely diagnosis and initiation of treatment, which in the long term will significantly affect their prognosis and quality of life.
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Affiliation(s)
- V. T. Ivashkin
- I.M. Sechenov First Moscow State Medical University (Sechenov University)
| | - O. M. Drapkina
- National Medical Research Center for Therapy and Preventive Medicine
| | - M. V. Maevskaya
- I.M. Sechenov First Moscow State Medical University (Sechenov University)
| | - K. L. Raikhelson
- Saint Petersburg State University;
Academician I.P. Pavlov First Saint Petersburg State Medical University
| | - S. V. Okovityi
- Saint Petersburg State Chemical Pharmaceutical University
| | - M. S. Zharkova
- I.M. Sechenov First Moscow State Medical University (Sechenov University)
| | | | | | | | - M. D. Ardatskaya
- Central State Medical Academy of the Department of Presidential Affairs
| | - I. G. Bakulin
- North-Western State Medical University named after I.I. Mechnikov
| | - N. V. Bakulina
- North-Western State Medical University named after I.I. Mechnikov
| | - P. O. Bogomolov
- Russian University of Medicine;
Moscow Regional Research Clinical Institute
| | - V. V. Breder
- National Medical Research Center of Oncology named after N.N. Blokhin
| | | | | | | | | | | | | | | | - K. B. Kodzoeva
- National Medical Research Center for Transplantology and Artificial Organs named after Academician V.I. Shumakov
| | - I. V. Kozlova
- Saratov State Medical University named after V.I. Razumovsky
| | | | | | | | | | | | | | | | | | - S. N. Mekhtiev
- Academician I.P. Pavlov First Saint Petersburg State Medical University
| | | | - M. Yu. Nadinskaia
- I.M. Sechenov First Moscow State Medical University (Sechenov University)
| | - I. G. Nikitin
- N.I. Pirogov Russian National Research Medical University;
National Medical Research Center “Treatment and Rehabilitation Center”
| | | | | | - Ch. S. Pavlov
- I.M. Sechenov First Moscow State Medical University (Sechenov University);
Moscow Multidisciplinary Scientific and Clinical Center named after S.P. Botkin
| | - N. V. Pogosova
- National Medical Research Center of Cardiology named after Academician E.I. Chazov
| | | | - G. E. Roytberg
- N.I. Pirogov Russian National Research Medical University
| | - R. G. Saifutdinov
- Kazan State Medical Academy — Branch Campus of the Russian Medical Academy of Continuous Professional Education
| | | | | | - S. I. Sitkin
- North-Western State Medical University named after I.I. Mechnikov;
V.A. Almazov National Medical Research Center
| | | | - A. I. Tarzimanova
- I.M. Sechenov First Moscow State Medical University (Sechenov University)
| | - O. N. Tkacheva
- N.I. Pirogov Russian National Research Medical University
| | | | | | | | - Yu. P. Uspenskiy
- Academician I.P. Pavlov First Saint Petersburg State Medical University;
Saint Petersburg State Pediatric Medical University
| | - Yu. A. Fominykh
- V.A. Almazov National Medical Research Center; Saint Petersburg State Pediatric Medical University
| | - O. V. Khlynova
- Perm State Medical University named after Academician E.A. Wagner
| | | | | | - O. O. Sharkhun
- N.I. Pirogov Russian National Research Medical University
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Geng W, Liao W, Cao X, Yang Y. Therapeutic Targets and Approaches to Manage Inflammation of NAFLD. Biomedicines 2025; 13:393. [PMID: 40002806 PMCID: PMC11853636 DOI: 10.3390/biomedicines13020393] [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: 12/23/2024] [Revised: 01/18/2025] [Accepted: 01/21/2025] [Indexed: 02/27/2025] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) and its advanced form, non-alcoholic steatohepatitis (NASH), are the leading causes of chronic liver disease globally. They are driven by complex mechanisms where inflammation plays a pivotal role in disease progression. Current therapies, including lifestyle changes and pharmacological agents, are limited in efficacy, particularly in addressing the advanced stages of the disease. Emerging approaches targeting inflammation, metabolic dysfunction, and fibrosis offer promising new directions, though challenges such as treatment complexity and heterogeneity persist. This review concludes the main therapeutic targets and approaches to manage inflammation currently and emphasizes the critical need for future drug development and combination therapy for NAFLD/NASH management.
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Affiliation(s)
- Wanying Geng
- 4+4 Medical Doctor Program, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100730, China;
- Department of Gastroenterology, Department of Internal Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100730, China; (W.L.); (X.C.)
| | - Wanying Liao
- Department of Gastroenterology, Department of Internal Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100730, China; (W.L.); (X.C.)
| | - Xinyuan Cao
- Department of Gastroenterology, Department of Internal Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100730, China; (W.L.); (X.C.)
| | - Yingyun Yang
- Department of Gastroenterology, Department of Internal Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100730, China; (W.L.); (X.C.)
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3
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Bril F, Berg G, Barchuk M, Nogueira JP. Practical Approaches to Managing Dyslipidemia in Patients With Metabolic Dysfunction-Associated Steatotic Liver Disease. J Lipid Atheroscler 2025; 14:5-29. [PMID: 39911965 PMCID: PMC11791423 DOI: 10.12997/jla.2025.14.1.5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2023] [Revised: 02/15/2024] [Accepted: 03/10/2024] [Indexed: 02/07/2025] Open
Abstract
Dyslipidemia is a major risk factor for cardiovascular disease, and its impact may be exacerbated when accompanied by metabolic dysfunction-associated steatotic liver disease (MASLD). The simultaneous management of these conditions poses multiple challenges for healthcare providers. Insulin resistance has been implicated in the pathogenesis of both dyslipidemia and MASLD, necessitating a holistic approach to managing dyslipidemia, glucose levels, body weight, and MASLD. This review explores the intricate pathophysiological relationship between MASLD and dyslipidemia. It also examines current guidance regarding the use of lipid-lowering agents (including statins, ezetimibe, fibrates, omega-3 polyunsaturated fatty acids, and proprotein convertase subtilisin/kexin type 9 inhibitors) as well as glucose-lowering medications (such as pioglitazone, glucagon-like peptide-1 receptor agonists, and sodium-glucose cotransporter 2 inhibitors) in patients with MASLD, with or without metabolic dysfunction-associated steatohepatitis (MASH), and dyslipidemia. Additionally, the review addresses the potential of emerging drugs to concurrently target both MASLD/MASH and dyslipidemia. Our hope is that a deeper understanding of the mechanisms underlying MASLD and dyslipidemia may assist clinicians in the management of these complex cases.
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Affiliation(s)
- Fernando Bril
- Division of Endocrinology, Diabetes and Metabolism, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Gabriela Berg
- Facultad de Farmacia y Bioquímica, Departamento de Bioquímica Clínica, Cátedra de Bioquímica Clínica I, Laboratorio de Lípidos y Aterosclerosis, Universidad de Buenos Aires, Buenos Aires, Argentina
- CONICET, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Magali Barchuk
- Facultad de Farmacia y Bioquímica, Departamento de Bioquímica Clínica, Cátedra de Bioquímica Clínica I, Laboratorio de Lípidos y Aterosclerosis, Universidad de Buenos Aires, Buenos Aires, Argentina
- CONICET, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Juan Patricio Nogueira
- Centro de Investigación en Endocrinología, Nutrición y Metabolismo (CIENM), Facultad de Ciencias de la Salud, Universidad Nacional de Formosa, Formosa, Argentina
- Universidad Internacional de las Américas, San José, Costa Rica
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Amorim R, Soares P, Chavarria D, Benfeito S, Cagide F, Teixeira J, Oliveira PJ, Borges F. Decreasing the burden of non-alcoholic fatty liver disease: From therapeutic targets to drug discovery opportunities. Eur J Med Chem 2024; 277:116723. [PMID: 39163775 DOI: 10.1016/j.ejmech.2024.116723] [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: 05/30/2024] [Revised: 07/24/2024] [Accepted: 07/25/2024] [Indexed: 08/22/2024]
Abstract
Non-alcoholic fatty liver disease (NAFLD) presents a pervasive global pandemic, affecting approximately 25 % of the world's population. This grave health issue not only demands urgent attention but also stands as a significant economic concern on a global scale. The genesis of NAFLD can be primarily attributed to unhealthy dietary habits and a sedentary lifestyle, albeit certain genetic factors have also been recorded to contribute to its occurrence. NAFLD is characterized by fat accumulation in more than 5 % of hepatocytes according to histological analysis, or >5.6 % of lipid volume fraction in total liver weight in patients. The pathophysiology of NAFLD/non-alcoholic steatohepatitis (NASH) is multifactorial and the mechanisms underlying the progression to advanced forms remain unclear, thereby representing a challenge to disease therapy. Despite the substantial efforts from the scientific community and the large number of pre-clinical and clinical trials performed so far, only one drug was approved by the Food and Drug Administration (FDA) to treat NAFLD/NASH specifically. This review provides an overview of available information concerning emerging molecular targets and drug candidates tested in clinical studies for the treatment of NAFLD/NASH. Improving our understanding of NAFLD pathophysiology and pharmacotherapy is crucial not only to explore new molecular targets, but also to potentiate drug discovery programs to develop new therapeutic strategies. This knowledge endeavours scientific efforts to reduce the time for achieving a specific and effective drug for NAFLD or NASH management and improve patients' quality of life.
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Affiliation(s)
- Ricardo Amorim
- CNC-UC, Center for Neuroscience and Cell Biology, University of Coimbra, Portugal; CIBB, Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, Portugal
| | - Pedro Soares
- CIQUP-IMS/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Porto, Portugal
| | - Daniel Chavarria
- CIQUP-IMS/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Porto, Portugal
| | - Sofia Benfeito
- CIQUP-IMS/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Porto, Portugal
| | - Fernando Cagide
- CIQUP-IMS/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Porto, Portugal
| | - José Teixeira
- CNC-UC, Center for Neuroscience and Cell Biology, University of Coimbra, Portugal; CIBB, Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, Portugal
| | - Paulo J Oliveira
- CNC-UC, Center for Neuroscience and Cell Biology, University of Coimbra, Portugal; CIBB, Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, Portugal.
| | - Fernanda Borges
- CIQUP-IMS/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Porto, Portugal.
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Bandyopadhyay S, Samajdar SS, Chaudhuri S, Das S. An insight into the updated pharmacotherapy of metabolic-associated fatty liver disease (MAFLD) or metabolic dysfunction-associated steatohepatitis (MASH) in lean individuals: a review. Hosp Pract (1995) 2024:1-7. [PMID: 39356238 DOI: 10.1080/21548331.2024.2412513] [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: 04/30/2024] [Revised: 09/22/2024] [Accepted: 10/01/2024] [Indexed: 10/03/2024]
Abstract
Metabolic-associated fatty liver disease (MAFLD) or metabolic dysfunction-associated steatohepatitis (MASH) in lean individuals represents a distinctive subset of MASH. Current pharmacotherapies, for MASH as demonstrated in clinical trials, predominantly target obese patients with limited consideration for lean MASH. We aimed to systematically review the literature on the pharmacotherapy of lean MASH. We searched standard medical databases, such as PubMed, Embase, Scopus, Cochrane CENTRAL, and ClinicalTrials.gov to identify eligible studies published in English up to 31 December 2023 regarding the effect of pharmacological interventions in individuals with lean MASH. We have summarized the role of various drug classes including peroxisome proliferator-activated receptor agonists, glucagon-like peptide-1 receptor agonists, sodium-glucose cotransporter 2 inhibitors, vitamin E, farnesoid X receptor agonists, selective thyroid hormone receptor-β agonists, and selective cholesterol absorption inhibitors. Consequently, lifestyle interventions, encompassing dietary modifications, exercise, and weight loss particularly directed at visceral obesity or achieving a reduction in body weight are recommended for all non-obese individuals with MASH. A highlight on the only available treatment recommendation for lean MASH is also presented. The available evidence regarding the efficacy of various drugs for the treatment of lean MASH is limited. Conclusive evidence is warranted from clinical trials exclusively involving lean individuals with MASH.
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Affiliation(s)
| | - Shambo Samrat Samajdar
- Department of Clinical and Experimental Pharmacology, Calcutta School of Tropical Medicine, Kolkata, India
| | | | - Saibal Das
- Indian Council of Medical Research - Centre for Ageing and Mental Health, Kolkata, India
- Department of Global Public Health, Karolinska Institutet, Stockholm, Sweden
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Elmakki EE. Deranged Liver Function Tests Associated With Hyperferritinemia in a Patient With Type 2 Diabetes Mellitus: A Case Study and Literature Review. Cureus 2024; 16:e66074. [PMID: 39229407 PMCID: PMC11368582 DOI: 10.7759/cureus.66074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/02/2024] [Indexed: 09/05/2024] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a common complication in patients with type 2 diabetes mellitus (T2DM), potentially progressing to more severe conditions such as metabolic dysfunction-associated steatohepatitis (MASH), liver cirrhosis, and hepatocellular carcinoma. This case study presents a 55-year-old man with long-standing T2DM who was found to have deranged liver function tests, elevated serum iron, and hyperferritinemia during a routine follow-up visit. The patient's clinical presentation, laboratory findings, and imaging results led to a diagnosis of MASH, complicated by dysregulated iron metabolism. This case highlights the importance of vigilant monitoring of liver function and iron studies in T2DM patients. Furthermore, it illustrates the challenges in managing the complex interplay between metabolic syndrome, liver dysfunction, and cardiovascular risk.
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Affiliation(s)
- Erwa Eltayib Elmakki
- Department of Internal Medicine, Faculty of Medicine, Jazan University, Jazan, SAU
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Butera E, Termite F, Esposto G, Galasso L, Mignini I, Borriello R, Ainora ME, Miele L, Gasbarrini A, Zocco MA. Exploring the Role of Bempedoic Acid in Metabolic Dysfunction Associated Steatotic Liver Disease: Actual Evidence and Future Perspectives. Int J Mol Sci 2024; 25:6938. [PMID: 39000046 PMCID: PMC11241610 DOI: 10.3390/ijms25136938] [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: 05/25/2024] [Revised: 06/20/2024] [Accepted: 06/22/2024] [Indexed: 07/14/2024] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) involves excessive lipid accumulation in hepatocytes, impacting global healthcare due to its high prevalence and risk of progression to severe liver conditions. Its pathogenesis involves genetic, metabolic, and inflammatory factors, with cardiovascular events as the leading cause of mortality. This review examines the role of lipid-lowering therapies in MASLD, with a particular focus on bempedoic acid, a recently approved cholesterol-lowering agent for hypercholesterolemia and high cardiovascular-risk patients. It explores its potential in liver disease by modulating lipid metabolism and inflammatory pathways based on the most recent studies available. Bempedoic acid inhibits ATP-citrate lyase, reducing cholesterol and fatty acid synthesis while activating AMP-activated protein kinase to suppress gluconeogenesis and lipogenesis. Animal studies indicate its efficacy in reducing hepatic steatosis, inflammation, and fibrosis. Bempedoic acid holds promise as a therapeutic for MASLD, offering dual benefits in lipid metabolism and inflammation. Further clinical trials are required to confirm its efficacy and safety in MASLD patients, potentially addressing the multifaceted nature of this disease.
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Affiliation(s)
- Elena Butera
- Internal Medicine, Fondazione Policlinico Universitario “A.Gemelli” IRCCS, Università Cattolica del Sacro Cuore, Rome 00168, Italy;
| | - Fabrizio Termite
- CEMAD Digestive Disease Center, Fondazione Policlinico Universitario “A.Gemelli” IRCCS, Università Cattolica del Sacro Cuore, Rome 00168, Italy; (F.T.); (G.E.); (L.G.); (I.M.); (R.B.); (M.E.A.); (L.M.); (A.G.)
| | - Giorgio Esposto
- CEMAD Digestive Disease Center, Fondazione Policlinico Universitario “A.Gemelli” IRCCS, Università Cattolica del Sacro Cuore, Rome 00168, Italy; (F.T.); (G.E.); (L.G.); (I.M.); (R.B.); (M.E.A.); (L.M.); (A.G.)
| | - Linda Galasso
- CEMAD Digestive Disease Center, Fondazione Policlinico Universitario “A.Gemelli” IRCCS, Università Cattolica del Sacro Cuore, Rome 00168, Italy; (F.T.); (G.E.); (L.G.); (I.M.); (R.B.); (M.E.A.); (L.M.); (A.G.)
| | - Irene Mignini
- CEMAD Digestive Disease Center, Fondazione Policlinico Universitario “A.Gemelli” IRCCS, Università Cattolica del Sacro Cuore, Rome 00168, Italy; (F.T.); (G.E.); (L.G.); (I.M.); (R.B.); (M.E.A.); (L.M.); (A.G.)
| | - Raffaele Borriello
- CEMAD Digestive Disease Center, Fondazione Policlinico Universitario “A.Gemelli” IRCCS, Università Cattolica del Sacro Cuore, Rome 00168, Italy; (F.T.); (G.E.); (L.G.); (I.M.); (R.B.); (M.E.A.); (L.M.); (A.G.)
| | - Maria Elena Ainora
- CEMAD Digestive Disease Center, Fondazione Policlinico Universitario “A.Gemelli” IRCCS, Università Cattolica del Sacro Cuore, Rome 00168, Italy; (F.T.); (G.E.); (L.G.); (I.M.); (R.B.); (M.E.A.); (L.M.); (A.G.)
| | - Luca Miele
- CEMAD Digestive Disease Center, Fondazione Policlinico Universitario “A.Gemelli” IRCCS, Università Cattolica del Sacro Cuore, Rome 00168, Italy; (F.T.); (G.E.); (L.G.); (I.M.); (R.B.); (M.E.A.); (L.M.); (A.G.)
| | - Antonio Gasbarrini
- CEMAD Digestive Disease Center, Fondazione Policlinico Universitario “A.Gemelli” IRCCS, Università Cattolica del Sacro Cuore, Rome 00168, Italy; (F.T.); (G.E.); (L.G.); (I.M.); (R.B.); (M.E.A.); (L.M.); (A.G.)
| | - Maria Assunta Zocco
- CEMAD Digestive Disease Center, Fondazione Policlinico Universitario “A.Gemelli” IRCCS, Università Cattolica del Sacro Cuore, Rome 00168, Italy; (F.T.); (G.E.); (L.G.); (I.M.); (R.B.); (M.E.A.); (L.M.); (A.G.)
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8
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Ali FEM, Abdel-Reheim MA, Hassanein EHM, Abd El-Aziz MK, Althagafy HS, Badran KSA. Exploring the potential of drug repurposing for liver diseases: A comprehensive study. Life Sci 2024; 347:122642. [PMID: 38641047 DOI: 10.1016/j.lfs.2024.122642] [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: 02/09/2024] [Revised: 03/24/2024] [Accepted: 04/10/2024] [Indexed: 04/21/2024]
Abstract
Drug repurposing involves the investigation of existing drugs for new indications. It offers a great opportunity to quickly identify a new drug candidate at a lower cost than novel discovery and development. Despite the importance and potential role of drug repurposing, there is no specific definition that healthcare providers and the World Health Organization credit. Unfortunately, many similar and interchangeable concepts are being used in the literature, making it difficult to collect and analyze uniform data on repurposed drugs. This research was conducted based on understanding general criteria for drug repurposing, concentrating on liver diseases. Many drugs have been investigated for their effect on liver diseases even though they were originally approved (or on their way to being approved) for other diseases. Some of the hypotheses for drug repurposing were first captured from the literature and then processed further to test the hypothesis. Recently, with the revolution in bioinformatics techniques, scientists have started to use drug libraries and computer systems that can analyze hundreds of drugs to give a short list of candidates to be analyzed pharmacologically. However, this study revealed that drug repurposing is a potential aid that may help deal with liver diseases. It provides available or under-investigated drugs that could help treat hepatitis, liver cirrhosis, Wilson disease, liver cancer, and fatty liver. However, many further studies are needed to ensure the efficacy of these drugs on a large scale.
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Affiliation(s)
- Fares E M Ali
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Assiut 71524, Egypt; Michael Sayegh, Faculty of Pharmacy, Aqaba University of Technology, Aqaba 77110, Jordan
| | - Mustafa Ahmed Abdel-Reheim
- Department of Pharmaceutical Sciences, College of Pharmacy, Shaqra University, Shaqra 11961, Saudi Arabia; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni Suef 62521, Egypt.
| | - Emad H M Hassanein
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Assiut 71524, Egypt.
| | - Mostafa K Abd El-Aziz
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Assiut 71524, Egypt
| | - Hanan S Althagafy
- Department of Biochemistry, Faculty of Science, University of Jeddah, Jeddah, Saudi Arabia
| | - Khalid S A Badran
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Assiut 71524, Egypt
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Zhang L, Shi Y, Liang B, Li X. An overview of the cholesterol metabolism and its proinflammatory role in the development of MASLD. Hepatol Commun 2024; 8:e0434. [PMID: 38696365 PMCID: PMC11068152 DOI: 10.1097/hc9.0000000000000434] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Accepted: 03/05/2024] [Indexed: 05/04/2024] Open
Abstract
Cholesterol is an essential lipid molecule in mammalian cells. It is not only involved in the formation of cell membranes but also serves as a raw material for the synthesis of bile acids, vitamin D, and steroid hormones. Additionally, it acts as a covalent modifier of proteins and plays a crucial role in numerous life processes. Generally, the metabolic processes of cholesterol absorption, synthesis, conversion, and efflux are strictly regulated. Excessive accumulation of cholesterol in the body is a risk factor for metabolic diseases such as cardiovascular disease, type 2 diabetes, and metabolic dysfunction-associated steatotic liver disease (MASLD). In this review, we first provide an overview of the discovery of cholesterol and the fundamental process of cholesterol metabolism. We then summarize the relationship between dietary cholesterol intake and the risk of developing MASLD, and also the animal models of MASLD specifically established with a cholesterol-containing diet. In the end, the role of cholesterol-induced inflammation in the initiation and development of MASLD is discussed.
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Affiliation(s)
- Linqiang Zhang
- Institute of Life Sciences, School of Basic Medicine, Chongqing Medical University, Chongqing, China
| | - Yongqiong Shi
- Institute of Life Sciences, School of Basic Medicine, Chongqing Medical University, Chongqing, China
| | - Bin Liang
- Center for Life Sciences, Yunnan Key Laboratory of Cell Metabolism and Diseases, School of Life Sciences, Yunnan University, Kunming, Yunnan, China
| | - Xi Li
- Institute of Life Sciences, School of Basic Medicine, Chongqing Medical University, Chongqing, China
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Hu Y, Li H, Zhang H, Chen X, Chen J, Xu Z, You H, Dong R, Peng Y, Li J, Li X, Wu D, Zhang L, Cao D, Jin H, Qiu D, Yang A, Lou J, Zhu X, Niu J, Ding Y. ZSP1601, a novel pan-phosphodiesterase inhibitor for the treatment of NAFLD, A randomized, placebo-controlled phase Ib/IIa trial. Nat Commun 2023; 14:6409. [PMID: 37828034 PMCID: PMC10570369 DOI: 10.1038/s41467-023-42162-0] [Citation(s) in RCA: 2] [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: 11/30/2022] [Accepted: 10/02/2023] [Indexed: 10/14/2023] Open
Abstract
Non-alcoholic fatty liver disease is a growing health burden with limited treatment options worldwide. Herein we report a randomized, double-blind, placebo-controlled, multiple-dose trial of a first-in-class pan-phosphodiesterase inhibitor ZSP1601 in 36 NAFLD patients (NCT04140123). There were three cohorts. Each cohort included twelve patients, nine of whom received ZSP1601 50 mg once daily, 50 mg twice daily, or 100 mg twice daily, and three of whom received matching placebos for 28 days. The primary outcomes were the safety and tolerability of ZSP1601. A total of 27 (27/36, 75%) patients experienced at least one treatment-emergent adverse event (TEAE). Most TEAEs were mild to moderate. There was no Serious Adverse Event. Diarrhea, transiently elevated creatinine and adaptive headache were frequently reported adverse drug reaction. We conclude that ZSP1601 is well-tolerated and safe, showing effective improvement in liver chemistries, liver fat content and fibrosis in patients with NAFLD.
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Affiliation(s)
- Yue Hu
- Phase I Clinical Research Center, First Hospital of Jilin University, Changchun, China
| | - Haijun Li
- Guangdong Raynovent Biotech Co., Ltd, Guangzhou, China
- Department of Anatomy and Neurobiology, School of Basic Medical Science, Central South University, Changsha, China
| | - Hong Zhang
- Phase I Clinical Research Center, First Hospital of Jilin University, Changchun, China
| | - Xiaoxin Chen
- Guangdong Raynovent Biotech Co., Ltd, Guangzhou, China
| | - Jinjun Chen
- Nafang Hospital, Nanfang Medical University, Guangzhou, China
| | - Zhongyuan Xu
- Nafang Hospital, Nanfang Medical University, Guangzhou, China
| | - Hong You
- Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Ruihua Dong
- Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Yun Peng
- Guangdong Raynovent Biotech Co., Ltd, Guangzhou, China
| | - Jing Li
- Guangdong Raynovent Biotech Co., Ltd, Guangzhou, China
| | - Xiaojiao Li
- Phase I Clinical Research Center, First Hospital of Jilin University, Changchun, China
| | - Dandan Wu
- Phase I Clinical Research Center, First Hospital of Jilin University, Changchun, China
| | - Lei Zhang
- Department of Radiology, First Hospital of Jilin University, Changchun, China
| | - Di Cao
- Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - He Jin
- Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Dongdong Qiu
- Department of Radiology, First Hospital of Jilin University, Changchun, China
| | - Aruhan Yang
- Phase I Clinical Research Center, First Hospital of Jilin University, Changchun, China
| | - Jinfeng Lou
- Phase I Clinical Research Center, First Hospital of Jilin University, Changchun, China
| | - Xiaoxue Zhu
- Phase I Clinical Research Center, First Hospital of Jilin University, Changchun, China.
| | - Junqi Niu
- Department of Hepatology, First Hospital of Jilin University, Changchun, China.
| | - Yanhua Ding
- Phase I Clinical Research Center, First Hospital of Jilin University, Changchun, China.
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11
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Pais R, Cariou B, Noureddin M, Francque S, Schattenberg JM, Abdelmalek MF, Lalazar G, Varma S, Dietrich J, Miller V, Sanyal A, Ratziu V. A proposal from the liver forum for the management of comorbidities in non-alcoholic steatohepatitis therapeutic trials. J Hepatol 2023; 79:829-841. [PMID: 37001695 DOI: 10.1016/j.jhep.2023.03.014] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 02/08/2023] [Accepted: 03/13/2023] [Indexed: 06/19/2023]
Abstract
The current document has been developed by the Liver Forum who mandated the NAFLD-Associated Comorbidities Working Group - a multistakeholder group comprised of experts from academic medicine, industry and patient associations - to identify aspects of diverse comorbidities frequently associated with non-alcoholic steatohepatitis (NASH) that can interfere with the conduct of therapeutic trials and, in particular, impact efficacy and safety results. The objective of this paper is to propose guidance for the management of relevant comorbidities in both candidates and actual participants in NASH therapeutic trials. We relied on specific guidelines from scientific societies, when available, but adapted them to the particulars of NASH trials with the aim of addressing multiple interacting requirements such as maintaining patient safety, reaching holistic therapeutic objectives, minimising confounding effects on efficacy and safety of investigational agents and allowing for trial completion. We divided the field of action into: first, analysis and stabilisation of the patient's condition before inclusion in the trial and, second, management of comorbidities during trial conduct. For the former, we discussed the concept of acceptable vs. optimal control of comorbidities, defined metabolic and ponderal stability prior to randomisation and weighed the pros and cons of a run-in period. For the latter, we analysed non-hepatological comorbid conditions for changes or acute events possibly occurring during the trial, including changes in alcohol consumption, in order to detail when specific interventions are necessary and how best to manage concomitant drug intake in line with methodological constraints. These recommendations are intended to act as a guide for clinical trialists and are open to further refinement when additional data become available.
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Affiliation(s)
- Raluca Pais
- Sorbonne Université, Assistance Publique-Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Institute of Cardiometabolism and Nutrition, France; Centre de Recherche Saint Antoine, INSERM UMRS_938 Paris, France
| | - Bertrand Cariou
- Nantes Université, CHU Nantes, CNRS, INSERM, l'institut du Thorax, F-44000 Nantes, France
| | | | - Sven Francque
- Department of Gastroenterology Hepatology, Antwerp University Hospital, Drie Eikenstraat 655, B-2650 Edegem, Belgium; InflaMed Centre of Excellence, Laboratory for Experimental Medicine and Paediatrics, Translational Sciences in Inflammation and Immunology, Faculty of Medicine and Health Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Wilrijk, Belgium European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Belgium
| | - Jörn M Schattenberg
- Metabolic Liver Research Program, I. Department of Medicine, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
| | - Manal F Abdelmalek
- Division of Gastroenterology and Hepatology, Duke University, Durham, NC, USA
| | - Gadi Lalazar
- Liver Unit, Digestive Disease Institute, Shaare Zedek Medical Center, Jerusalem, Israel
| | - Sharat Varma
- Novo Nordisk A/S, Vandtårnsvej 108-110, 2860 Søborg Denmark
| | - Julie Dietrich
- GENFIT, Parc Eurasanté 885, Avenue Eugène Avinée, 59120, Loos, France
| | - Veronica Miller
- Forum for Collaborative Research, University of California Berkeley School of Public Health, Washington D.C., USA
| | - Arun Sanyal
- Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
| | - Vlad Ratziu
- Sorbonne Université, Assistance Publique-Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Institute of Cardiometabolism and Nutrition, France; INSERM UMRS 1138 CRC, Paris, France.
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12
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Noureddin M, Abdelmalek MF. Current Treatment Options, Including Diet, Exercise, and Medications: The Impact on Histology. Clin Liver Dis 2023; 27:397-412. [PMID: 37024215 DOI: 10.1016/j.cld.2023.01.008] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/08/2023]
Abstract
Paralleling the rise in obesity and diabetes, nonalcoholic fatty liver disease (NAFLD) is now the most prevalent chronic liver disease worldwide. Nonalcoholic steatohepatitis (NASH), the progressive form of NAFLD, may progress to cirrhosis, hepatic decompensation, and hepatocellular carcinoma. Despite its public health treat, no approved pharmacotherapies for NAFLD/NASH currently exist. Although the armamentarium of therapies for NASH is limited, current treatment options include life-style modification and the use of medications to treat metabolic comorbidities. This review addresses current approaches to the treatment of NAFLD/NASH, including the impact of diet, exercise, and available pharmacotherapies on the histologic features of liver injury.
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Affiliation(s)
- Mazen Noureddin
- Sherrie and Alan Conover Center for Liver Disease and Transplantation, Houston Methodist Hospital, Houston, TX, USA; Houston Research Institute and Houston Liver Institute, Houston, TX, USA
| | - Manal F Abdelmalek
- Division of Gastroenterology & Hepatology, Department of Medicine, Mayo Clinic, Rochester, MN, USA.
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13
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Tsamos G, Vasdeki D, Koufakis T, Michou V, Makedou K, Tzimagiorgis G. Therapeutic Potentials of Reducing Liver Fat in Non-Alcoholic Fatty Liver Disease: Close Association with Type 2 Diabetes. Metabolites 2023; 13:metabo13040517. [PMID: 37110175 PMCID: PMC10141666 DOI: 10.3390/metabo13040517] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2023] [Revised: 03/21/2023] [Accepted: 03/29/2023] [Indexed: 04/29/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD), the most widespread chronic liver disease worldwide, confers a significant burden on health systems and leads to increased mortality and morbidity through several extrahepatic complications. NAFLD comprises a broad spectrum of liver-related disorders, including steatosis, cirrhosis, and hepatocellular carcinoma. It affects almost 30% of adults in the general population and up to 70% of people with type 2 diabetes (T2DM), sharing common pathogenetic pathways with the latter. In addition, NAFLD is closely related to obesity, which acts in synergy with other predisposing conditions, including alcohol consumption, provoking progressive and insidious liver damage. Among the most potent risk factors for accelerating the progression of NAFLD to fibrosis or cirrhosis, diabetes stands out. Despite the rapid rise in NAFLD rates, identifying the optimal treatment remains a challenge. Interestingly, NAFLD amelioration or remission appears to be associated with a lower risk of T2DM, indicating that liver-centric therapies could reduce the risk of developing T2DM and vice versa. Consequently, assessing NAFLD requires a multidisciplinary approach to identify and manage this multisystemic clinical entity early. With the continuously emerging new evidence, innovative therapeutic strategies are being developed for the treatment of NAFLD, prioritizing a combination of lifestyle changes and glucose-lowering medications. Based on recent evidence, this review scrutinizes all practical and sustainable interventions to achieve a resolution of NAFLD through a multimodal approach.
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Affiliation(s)
- Georgios Tsamos
- Division of Gastroenterology, Norfolk and Norwich University Hospital, Norwich NR4 7UY, UK
| | - Dimitra Vasdeki
- Division of Endocrinology and Metabolism and Diabetes Center, First Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA University Hospital, 54636 Thessaloniki, Greece
| | - Theocharis Koufakis
- Division of Endocrinology and Metabolism and Diabetes Center, First Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA University Hospital, 54636 Thessaloniki, Greece
| | - Vassiliki Michou
- Sports Medicine Laboratory, School of Physical Education & Sport Science, Aristotle University of Thessaloniki, 57001 Thessaloniki, Greece
| | - Kali Makedou
- Laboratory of Biological Chemistry, Medical School, Aristotle University of Thessaloniki, AHEPA University Hospital, 54636 Thessaloniki, Greece
| | - Georgios Tzimagiorgis
- Laboratory of Biological Chemistry, Medical School, Aristotle University of Thessaloniki, AHEPA University Hospital, 54636 Thessaloniki, Greece
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14
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Licata A, Russo GT, Giandalia A, Cammilleri M, Asero C, Cacciola I. Impact of Sex and Gender on Clinical Management of Patients with Advanced Chronic Liver Disease and Type 2 Diabetes. J Pers Med 2023; 13:jpm13030558. [PMID: 36983739 PMCID: PMC10051396 DOI: 10.3390/jpm13030558] [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: 12/28/2022] [Revised: 02/22/2023] [Accepted: 03/13/2023] [Indexed: 03/30/2023] Open
Abstract
Gender differences in the epidemiology, pathophysiological mechanisms and clinical features in chronic liver diseases that may be associated with type 2 diabetes (T2D) have been increasingly reported in recent years. This sexual dimorphism is due to a complex interaction between sex- and gender-related factors, including biological, hormonal, psychological and socio-cultural variables. However, the impact of sex and gender on the management of T2D subjects with liver disease is still unclear. In this regard, sex-related differences deserve careful consideration in pharmacology, aimed at improving drug safety and optimising medical therapy, both in men and women with T2D; moreover, low adherence to and persistence of long-term drug treatment is more common among women. A better understanding of sex- and gender-related differences in this field would provide an opportunity for a tailored diagnostic and therapeutic approach to the management of T2D subjects with chronic liver disease. In this narrative review, we summarized available data on sex- and gender-related differences in chronic liver disease, including metabolic, autoimmune, alcoholic and virus-related forms and their potential evolution towards cirrhosis and/or hepatocarcinoma in T2D subjects, to support their appropriate and personalized clinical management.
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Affiliation(s)
- Anna Licata
- Internal Medicine & Hepatology Unit, University Hospital of Palermo, PROMISE, University of Palermo, 90127 Palermo, Italy
| | - Giuseppina T Russo
- Internal Medicine and Diabetology Unit, University of Messina, 98125 Messina, Italy
| | - Annalisa Giandalia
- Internal Medicine and Hepatology Unit, University Hospital of Messina, 98124 Messina, Italy
- Department of Clinical and Experimental Medicine, University of Messina, 98124 Messina, Italy
| | - Marcella Cammilleri
- Internal Medicine & Hepatology Unit, University Hospital of Palermo, PROMISE, University of Palermo, 90127 Palermo, Italy
| | - Clelia Asero
- Internal Medicine and Hepatology Unit, University Hospital of Messina, 98124 Messina, Italy
- Department of Clinical and Experimental Medicine, University of Messina, 98124 Messina, Italy
| | - Irene Cacciola
- Internal Medicine and Hepatology Unit, University Hospital of Messina, 98124 Messina, Italy
- Department of Clinical and Experimental Medicine, University of Messina, 98124 Messina, Italy
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15
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Josloff K, Beiriger J, Khan A, Gawel RJ, Kirby RS, Kendrick AD, Rao AK, Wang RX, Schafer MM, Pearce ME, Chauhan K, Shah YB, Marhefka GD, Halegoua-DeMarzio D. Comprehensive Review of Cardiovascular Disease Risk in Nonalcoholic Fatty Liver Disease. J Cardiovasc Dev Dis 2022; 9:419. [PMID: 36547416 PMCID: PMC9786069 DOI: 10.3390/jcdd9120419] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2022] [Revised: 11/16/2022] [Accepted: 11/23/2022] [Indexed: 11/29/2022] Open
Abstract
Nonalcoholic Fatty Liver Disease (NAFLD) is a growing global phenomenon, and its damaging effects in terms of cardiovascular disease (CVD) risk are becoming more apparent. NAFLD is estimated to affect around one quarter of the world population and is often comorbid with other metabolic disorders including diabetes mellitus, hypertension, coronary artery disease, and metabolic syndrome. In this review, we examine the current evidence describing the many ways that NAFLD itself increases CVD risk. We also discuss the emerging and complex biochemical relationship between NAFLD and its common comorbid conditions, and how they coalesce to increase CVD risk. With NAFLD's rising prevalence and deleterious effects on the cardiovascular system, a complete understanding of the disease must be undertaken, as well as effective strategies to prevent and treat its common comorbid conditions.
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Affiliation(s)
- Kevan Josloff
- Sidney Kimmel Medical College, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Jacob Beiriger
- Sidney Kimmel Medical College, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Adnan Khan
- Department of Internal Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Richard J. Gawel
- Sidney Kimmel Medical College, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Richard S. Kirby
- Sidney Kimmel Medical College, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Aaron D. Kendrick
- Sidney Kimmel Medical College, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Abhinav K. Rao
- Sidney Kimmel Medical College, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Roy X. Wang
- Sidney Kimmel Medical College, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Michelle M. Schafer
- Sidney Kimmel Medical College, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Margaret E. Pearce
- Sidney Kimmel Medical College, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Kashyap Chauhan
- Department of Internal Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Yash B. Shah
- Sidney Kimmel Medical College, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Gregary D. Marhefka
- Department of Internal Medicine, Division of Cardiology, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Dina Halegoua-DeMarzio
- Department of Internal Medicine, Division of Gastroenterology & Hepatology, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
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16
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Ivashkin VT, Maevskaya MV, Zharkova MS, Kotovskaya YV, Tkacheva ON, Troshina EA, Shestakova MV, Maev IV, Breder VV, Gheivandova NI, Doshchitsin VL, Dudinskaya EN, Ershova EV, Kodzoeva KB, Komshilova KA, Korochanskaya NV, Mayorov AY, Mishina EE, Nadinskaya MY, Nikitin IG, Pogosova NV, Tarzimanova AI, Shamkhalova MS. Clinical Practice Guidelines of the Russian Scientific Liver Society, Russian Gastroenterological Association, Russian Association of Endocrinologists, Russian Association of Gerontologists and Geriatricians and National Society for Preventive Cardiology on Diagnosis and Treatment of Non-Alcoholic Liver Disease. RUSSIAN JOURNAL OF GASTROENTEROLOGY, HEPATOLOGY, COLOPROCTOLOGY 2022; 32:104-140. [DOI: 10.22416/1382-4376-2022-32-4-104-140] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Aim:present clinical guidelines, aimed at general practitioners, gastroenterologists, cardiologists, endocrinologists, comprise up-to-date methods of diagnosis and treatment of non-alcoholic fatty liver disease.Key points.Nonalcoholic fatty liver disease, the most wide-spread chronic liver disease, is characterized by accumulation of fat by more than 5 % of hepatocytes and presented by two histological forms: steatosis and nonalcoholic steatohepatitis. Clinical guidelines provide current views on pathogenesis of nonalcoholic fatty liver disease as a multisystem disease, methods of invasive and noninvasive diagnosis of steatosis and liver fibrosis, principles of nondrug treatment and pharmacotherapy of nonalcoholic fatty liver disease and associated conditions. Complications of nonalcoholic fatty liver disease include aggravation of cardiometabolic risks, development of hepatocellular cancer, progression of liver fibrosis to cirrhotic stage.Conclusion.Progression of liver disease can be avoided, cardiometabolic risks can be reduced and patients' prognosis — improved by the timely recognition of diagnosis of nonalcoholic fatty liver disease and associated comorbidities and competent multidisciplinary management of these patients.
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Affiliation(s)
| | | | | | - Yu. V. Kotovskaya
- Russian Gerontology Research and Clinical Centre, Pirogov Russian National Research Medical University
| | - O. N. Tkacheva
- Russian Gerontology Research and Clinical Centre, Pirogov Russian National Research Medical University
| | | | | | - I. V. Maev
- Yevdokimov Moscow State University of Medicine and Dentistry
| | - V. V. Breder
- Blokhin National Medical Research Center of Oncology
| | | | | | - E. N. Dudinskaya
- Russian Gerontology Research and Clinical Centre, Pirogov Russian National Research Medical University
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17
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Martin A, Lang S, Goeser T, Demir M, Steffen HM, Kasper P. Management of Dyslipidemia in Patients with Non-Alcoholic Fatty Liver Disease. Curr Atheroscler Rep 2022; 24:533-546. [PMID: 35507279 PMCID: PMC9236990 DOI: 10.1007/s11883-022-01028-4] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/13/2022] [Indexed: 02/08/2023]
Abstract
PURPOSE OF REVIEW Patients with non-alcoholic fatty liver disease (NAFLD), often considered as the hepatic manifestation of the metabolic syndrome, represent a population at high cardiovascular risk and frequently suffer from atherogenic dyslipidemia. This article reviews the pathogenic interrelationship between NAFLD and dyslipidemia, elucidates underlying pathophysiological mechanisms and focuses on management approaches for dyslipidemic patients with NAFLD. RECENT FINDINGS Atherogenic dyslipidemia in patients with NAFLD results from hepatic and peripheral insulin resistance along with associated alterations of hepatic glucose and lipoprotein metabolism, gut dysbiosis, and genetic factors. Since atherogenic dyslipidemia and NAFLD share a bi-directional relationship and are both major driving forces of atherosclerotic cardiovascular disease (ASCVD) development, early detection and adequate treatment are warranted. Thus, integrative screening and management programs are urgently needed. A stepwise approach for dyslipidemic patients with NAFLD includes (i) characterization of dyslipidemia phenotype, (ii) individual risk stratification, (iii) definition of treatment targets, (iv) lifestyle modification, and (v) pharmacotherapy if indicated.
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Affiliation(s)
- Anna Martin
- Clinic for Gastroenterology and Hepatology, Faculty of Medicine - University Hospital Cologne, University of Cologne, Kerpener Str. 62, 50937 Cologne, Germany
| | - Sonja Lang
- Clinic for Gastroenterology and Hepatology, Faculty of Medicine - University Hospital Cologne, University of Cologne, Kerpener Str. 62, 50937 Cologne, Germany
| | - Tobias Goeser
- Clinic for Gastroenterology and Hepatology, Faculty of Medicine - University Hospital Cologne, University of Cologne, Kerpener Str. 62, 50937 Cologne, Germany
| | - Münevver Demir
- Department of Hepatology and Gastroenterology, Campus Virchow Clinic, Charité University Medicine, Berlin, Germany
| | - Hans-Michael Steffen
- Clinic for Gastroenterology and Hepatology, Faculty of Medicine - University Hospital Cologne, University of Cologne, Kerpener Str. 62, 50937 Cologne, Germany
- Hypertension Center, Faculty of Medicine - University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Philipp Kasper
- Clinic for Gastroenterology and Hepatology, Faculty of Medicine - University Hospital Cologne, University of Cologne, Kerpener Str. 62, 50937 Cologne, Germany
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18
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Association of Metabolomic Change and Treatment Response in Patients with Non-Alcoholic Fatty Liver Disease. Biomedicines 2022; 10:biomedicines10061216. [PMID: 35740238 PMCID: PMC9220113 DOI: 10.3390/biomedicines10061216] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Revised: 05/19/2022] [Accepted: 05/20/2022] [Indexed: 01/27/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the major cause of chronic liver disease, yet cost-effective and non-invasive diagnostic tools to monitor the severity of the disease are lacking. We aimed to investigate the metabolomic changes in NAFLD associated with therapeutic responses. It was conducted in 63 patients with NAFLD who received either ezetimibe plus rosuvastatin or rosuvastatin monotherapy. The treatment response was determined by MRI performed at baseline and week 24. The metabolites were measured at baseline and week 12. In the combination group, a relative decrease in xanthine was associated with a good response to liver fat decrease, while a relative increase in choline was associated with a good response to liver stiffness. In the monotherapy group, the relative decreases in triglyceride (TG) 20:5_36:2, TG 18:1_38:6, acetylcarnitine (C2), fatty acid (FA) 18:2, FA 18:1, and docosahexaenoic acid were associated with a decrease in liver fat, while hexosylceramide (d18:2/16:0) and hippuric acid were associated with a decrease in liver stiffness. Models using the metabolite changes showed an AUC of >0.75 in receiver operating curve analysis for predicting an improvement in liver fat and stiffness. This approach revealed the physiological impact of drugs, suggesting the mechanism underlying the development of this disease.
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19
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Noto D, Petta S, Giammanco A, Spina R, Cabibbi D, Porcasi R, Caldarella R, Ciaccio M, Muratore R, Cefalù AB, Craxi A, Averna M. Lifestyle versus ezetimibe plus lifestyle in patients with biopsy-proven non-alcoholic steatohepatitis (LISTEN): A double-blind randomised placebo-controlled trial. Nutr Metab Cardiovasc Dis 2022; 32:1288-1291. [PMID: 35256232 DOI: 10.1016/j.numecd.2022.01.024] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 01/18/2022] [Accepted: 01/18/2022] [Indexed: 10/19/2022]
Abstract
BACKGROUND AND AIMS The LISTEN trial (ClinicalTrial.gov accession: NCT01950884) is a phase IV 52 weeks double blind parallel randomized controlled trial that evaluated the effect of ezetimibe plus lifestyle and dietary intervention (eze) vs. lifestyle and dietary intervention alone (placebo) on progression and complications of non-alcoholic steatohepatitis (NASH) evaluated by liver histology. METHODS AND RESULTS Forty patients with NASH ascertained by histology were randomly allocated on the two study groups and subjected to a follow-up of 52 weeks, when they underwent a second liver biopsy. Main composite end point (EP) was based on the histological improvement in the severity of NASH. Thirty patients completed the study, Eze treatment was not able to improve the primary EP in comparison with placebo, with and odds ratio of 1.029 (0.18-6.38), p = 0.974. Treatment emergent adverse events registered during the study were not more prevalent in the treatment arm. CONCLUSIONS ezetimibe administered on top of lifestyle and dietary modification failed to improve the histology of NASH in comparison with lifestyle and dietary modification alone. TRIAL ACCESSION NUMBER ClinicalTrial.gov: NCT01950884.
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Affiliation(s)
- Davide Noto
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy.
| | - Salvatore Petta
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy
| | - Antonina Giammanco
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy
| | - Rossella Spina
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy
| | - Daniela Cabibbi
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy
| | - Rossana Porcasi
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy
| | - Rosalia Caldarella
- Department of Biomedicine, Neurosciences and Advanced Diagnostics, University of Palermo, Palermo, Italy
| | - Marcello Ciaccio
- Department of Biomedicine, Neurosciences and Advanced Diagnostics, University of Palermo, Palermo, Italy
| | - Roberto Muratore
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy
| | - Angelo B Cefalù
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy
| | - Antonio Craxi
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy
| | - Maurizio Averna
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy; Istituto di Biofisica, Consiglio Nazionale delle Ricerche, Palermo, Italy.
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Maevskaya M, Kotovskaya Y, Ivashkin V, Tkacheva O, Troshina E, Shestakova M, Breder V, Geyvandova N, Doschitsin V, Dudinskaya E, Ershova E, Kodzoeva K, Komshilova K, Korochanskaya N, Mayorov A, Mishina E, Nadinskaya M, Nikitin I, Pogosova N, Tarzimanova A, Shamkhalova M. The National Consensus statement on the management of adult patients with non-alcoholic fatty liver disease and main comorbidities. TERAPEVT ARKH 2022; 94:216-253. [PMID: 36286746 DOI: 10.26442/00403660.2022.02.201363] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Indexed: 12/15/2022]
Abstract
The National Consensus was prepared with the participation of the National Medical Association for the Study of the Multimorbidity, Russian Scientific Liver Society, Russian Association of Endocrinologists, Russian Association of Gerontologists and Geriatricians, National Society for Preventive Cardiology, Professional Foundation for the Promotion of Medicine Fund PROFMEDFORUM.
The aim of the multidisciplinary consensus is a detailed analysis of the course of non-alcoholic fatty liver disease (NAFLD) and the main associated conditions. The definition of NAFLD is given, its prevalence is described, methods for diagnosing its components such as steatosis, inflammation and fibrosis are described.
The association of NAFLD with a number of cardio-metabolic diseases (arterial hypertension, atherosclerosis, thrombotic complications, type 2 diabetes mellitus (T2DM), obesity, dyslipidemia, etc.), chronic kidney disease (CKD) and the risk of developing hepatocellular cancer (HCC) were analyzed. The review of non-drug methods of treatment of NAFLD and modern opportunities of pharmacotherapy are presented.
The possibilities of new molecules in the treatment of NAFLD are considered: agonists of nuclear receptors, antagonists of pro-inflammatory molecules, etc. The positive properties and disadvantages of currently used drugs (vitamin E, thiazolidinediones, etc.) are described. Special attention is paid to the multi-target ursodeoxycholic acid (UDCA) molecule in the complex treatment of NAFLD as a multifactorial disease. Its anti-inflammatory, anti-oxidant and cytoprotective properties, the ability to reduce steatosis an independent risk factor for the development of cardiovascular pathology, reduce inflammation and hepatic fibrosis through the modulation of autophagy are considered.
The ability of UDCA to influence glucose and lipid homeostasis and to have an anticarcinogenic effect has been demonstrated. The Consensus statement has advanced provisions for practitioners to optimize the diagnosis and treatment of NAFLD and related common pathogenetic links of cardio-metabolic diseases.
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21
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Tzanaki I, Agouridis AP, Kostapanos MS. Is there a role of lipid-lowering therapies in the management of fatty liver disease? World J Hepatol 2022; 14:119-139. [PMID: 35126843 PMCID: PMC8790403 DOI: 10.4254/wjh.v14.i1.119] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Revised: 08/30/2021] [Accepted: 12/07/2021] [Indexed: 02/06/2023] Open
Abstract
Atherogenic dyslipidemia is characterized by increased triglyceride-rich lipoproteins and low high-density lipoprotein cholesterol concentrations. It is highly prevalent in non-alcoholic fatty liver disease (NAFLD) and contributes to the increased cardiovascular risk associated with this condition. Alongside insulin resistance it plays an important pathogenetic role in NAFLD/non-alcoholic steatohepatitis (NASH) development and progression. It has been shown that cholesterol-lowering reduces cardiovascular risk more in NAFLD vs non-NAFLD high-risk individuals. This evidence highlights the importance of effective lipid modulation in NAFLD. In this narrative review the effects of the most commonly used lipid-lowering therapies on liver outcomes alongside their therapeutic implications in NAFLD/NASH are critically discussed. Preclinical and clinical evidence suggests that statins reduce hepatic steatosis, inflammation and fibrosis in patients with NAFLD/NASH. Most data are derived from observational and small prospective clinical studies using changes in liver enzyme activities, steatosis/fibrosis scores, and imaging evidence of steatosis as surrogates. Also, relevant histologic benefits were noted in small biopsy studies. Atorvastatin and rosuvastatin showed greater benefits, whereas data for other statins are scarce and sometimes conflicting. Similar studies to those of statins showed efficacy of ezetimibe against hepatic steatosis. However, no significant anti-inflammatory and anti-fibrotic actions of ezetimibe have been shown. Preclinical studies showed that fibrates through peroxisome proliferator-activated receptor (PPAR)α activation may have a role in NAFLD prevention and management. Nevertheless, no relevant benefits have been noted in human studies. Species-related differences in PPARα expression and its activation responsiveness may help explain this discrepancy. Omega-3 fatty acids reduced hepatic steatosis in numerous heterogeneous studies, but their benefits on hepatic inflammation and fibrosis have not been established. Promising preliminary data for the highly purified eicosapentaenoic acid require further confirmation. Observational studies suggest that proprotein convertase subtilisin/kexin9 inhibitors may also have a role in the management of NAFLD, though this needs to be established by future prospective studies.
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Affiliation(s)
- Ismini Tzanaki
- School of Medicine, European University Cyprus, Nicosia, Cyprus, Nicosia 2404, Cyprus
| | - Aris P Agouridis
- School of Medicine, European University Cyprus, Nicosia 2404, Cyprus
| | - Michael S Kostapanos
- General Medicine, Addenbrooke's Hospital, Cambridge University Hospitals, Cambridge CB20QQ, United Kingdom.
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22
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Kim SH, Lee SJ, Yu SM. Study of lipid proton difference evaluation via 9.4T MRI analysis of fatty liver induced by exposure to methionine and choline-deficient (MCD) diet and high-fat diet (HFD) in an animal model. Chem Phys Lipids 2021; 242:105164. [PMID: 34906552 DOI: 10.1016/j.chemphyslip.2021.105164] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Revised: 10/25/2021] [Accepted: 12/09/2021] [Indexed: 12/20/2022]
Abstract
The selection of an animal model is based on the pathological mechanism appropriate for experimental investigation because the therapeutic effect was low depending on the pathological occurrence mechanism. The purpose of this study is to elucidate the changes in lipid proton concentration in two animal models of nonalcoholic fatty liver disease (NAFLD): methionine and choline-deficient (MCD) diet and high-fat diet (HFD). We calculated the T2 relaxation time of 7 lipid protons (LP) in the 9.4 T MRS phantom experiment. The concentrations of LPs were adjusted for T2 and T2* of MCD, HFD, and CCl4 fatty liver animal models. Multivariate analysis and Pearson correlation were performed to analyze LP concentration, and the difference was investigated via Kendall correlation and independent t-test using LP composition ratio. The T2 relaxation time of each LP was accurately determined using phantom experiments. The in vivo magnetic resonance spectroscopy (MRS) data were obtained by quantifying the t2/t2* corrected LP concentration in the liver of the animal model. In case of MCD and HFD, there was an average difference in all LPs except 0.9 ppm LP, and the MCD and CCl4 groups showed differences in the average of all LPs. However, there was no difference between LP of HFD and CCl4 groups. A higher level of unsaturated fatty acids was found in the MCD fatty liver model than in HFD induced fatty liver.
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Affiliation(s)
- Sang-Hyeok Kim
- Department of Radiological Science, College of Medical Sciences, Jeonju University, Jeonju city 55069, Republic of Korea
| | - Suk-Jun Lee
- Department of Biomedical Laboratory Science, College of Health Science, Cheongju University, Cheongju 360-764, Republic of Korea
| | - Seung-Man Yu
- Department of Radiological Science, College of Medical Sciences, Jeonju University, Jeonju city 55069, Republic of Korea.
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23
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Zhou F, Sun X. Cholesterol Metabolism: A Double-Edged Sword in Hepatocellular Carcinoma. Front Cell Dev Biol 2021; 9:762828. [PMID: 34869352 PMCID: PMC8635701 DOI: 10.3389/fcell.2021.762828] [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: 08/22/2021] [Accepted: 10/27/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) represents a leading cause of cancer-related deaths globally. The rising incidence of metabolic syndrome and its hepatic manifestation, nonalcoholic fatty liver disease (NAFLD), have emerged as the fastest-growing cause of HCC in recent years. Cholesterol, a major lipid component of the cell membrane and lipoprotein particles, is primarily produced and metabolized by the liver. Numerous studies have revealed an increased cholesterol biosynthesis and uptake, reduced cholesterol exportation and excretion in HCC, which all contribute to lipotoxicity, inflammation, and fibrosis, known HCC risk factors. In contrast, some clinical studies have shown that higher cholesterol is associated with a reduced risk of HCC. These contradictory observations imply that the relationship between cholesterol and HCC is far more complex than initially anticipated. Understanding the role of cholesterol and deciphering the underlying molecular events in HCC development is highly relevant to developing new therapies. Here, we discuss the current understanding of cholesterol metabolism in the pathogenesis of NAFLD-associated HCC, and the underlying mechanisms, including the roles of cholesterol in the disruption of normal function of specific cell types and signaling transduction. We also review the clinical progression in evaluating the association of cholesterol with HCC. The therapeutic effects of lowering cholesterol will also be summarized. We also interpret reasons for the contradictory observations from different preclinical and human studies of the roles of cholesterol in HCC, aiming to provide a critical assessment of the potential of cholesterol as a therapeutic target.
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Affiliation(s)
- Fangli Zhou
- Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, China
| | - Xiaoli Sun
- Department of Pharmacology, Mays Cancer Center, Transplant Center, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States
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24
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Yang JW, Ji HF. Phytosterols as bioactive food components against nonalcoholic fatty liver disease. Crit Rev Food Sci Nutr 2021:1-12. [PMID: 34871105 DOI: 10.1080/10408398.2021.2006137] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Phytosterols are bioactive food components widely present in cell membranes of plants, especially in nuts and oilseeds. In recent years, many studies have shown that phytosterols possess therapeutic potentials for nonalcoholic fatty liver disease (NAFLD). This review summarizes the effects of phytosterols from in vitro and in vivo studies to lower the levels of total cholesterol (TC) and triglycerides (TG), and the evidence supporting the potential of phytosterols against NAFLD. The potential mechanisms by which phytosterols improve NAFLD may include (i) competition with cholesterol; (ii) regulation of key factors involved in cholesterol and TG metabolism; and (iii) inhibition of liver inflammation and (iv) regulation of liver fatty acid composition. In summary, phytosterols are potential natural ingredients with good safety profile against NAFLD, which deserve more future studies.
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Affiliation(s)
- Jing-Wen Yang
- Institute of Biomedical Research, Shandong University of Technology, Zibo, Shandong, People's Republic of China.,Shandong Provincial Research Center for Bioinformatic Engineering and Technique, Zibo Key Laboratory of New Drug Development of Neurodegenerative diseases, School of Life Sciences, Shandong University of Technology, Zibo, Shandong, People's Republic of China
| | - Hong-Fang Ji
- Institute of Biomedical Research, Shandong University of Technology, Zibo, Shandong, People's Republic of China.,Shandong Provincial Research Center for Bioinformatic Engineering and Technique, Zibo Key Laboratory of New Drug Development of Neurodegenerative diseases, School of Life Sciences, Shandong University of Technology, Zibo, Shandong, People's Republic of China
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25
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Willis SA, Bawden SJ, Malaikah S, Sargeant JA, Stensel DJ, Aithal GP, King JA. The role of hepatic lipid composition in obesity-related metabolic disease. Liver Int 2021; 41:2819-2835. [PMID: 34547171 DOI: 10.1111/liv.15059] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 09/15/2021] [Accepted: 09/17/2021] [Indexed: 12/14/2022]
Abstract
Obesity is a primary antecedent to non-alcoholic fatty liver disease whose cardinal feature is excessive hepatic lipid accumulation. Although total hepatic lipid content closely associates with hepatic and systemic metabolic dysfunction, accumulating evidence suggests that the composition of hepatic lipids may be more discriminatory. This review summarises cross-sectional human studies using liver biopsy/lipidomics and proton magnetic resonance spectroscopy to characterise hepatic lipid composition in people with obesity and related metabolic disease. A comprehensive literature search identified 26 relevant studies published up to 31st March 2021 which were included in the review. The available evidence provides a consistent picture showing that people with hepatic steatosis possess elevated saturated and/or monounsaturated hepatic lipids and a reduced proportion of polyunsaturated hepatic lipids. This altered hepatic lipid profile associates more directly with metabolic derangements, such as insulin resistance, and may be exacerbated in non-alcoholic steatohepatitis. Further evidence from lipidomic studies suggests that these deleterious changes may be related to defects in lipid desaturation and elongation, and an augmentation of the de novo lipogenic pathway. These observations are consistent with mechanistic studies implicating saturated fatty acids and associated bioactive lipid intermediates (ceramides, lysophosphatidylcholines and diacylglycerol) in the development of hepatic lipotoxicity and wider metabolic dysfunction, whilst monounsaturated fatty acids and polyunsaturated fatty acids may exhibit a protective role. Future studies are needed to prospectively determine the relevance of hepatic lipid composition for hepatic and non-hepatic morbidity and mortality; and to further evaluate the impact of therapeutic interventions such as pharmacotherapy and lifestyle interventions.
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Affiliation(s)
- Scott A Willis
- National Centre for Sport and Exercise Medicine, School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, UK.,NIHR Leicester Biomedical Research Centre, University Hospitals of Leicester NHS Trust and University of Leicester, Leicester, UK
| | - Stephen J Bawden
- Sir Peter Mansfield Imaging Centre, University of Nottingham, Nottingham, UK.,NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and the University of Nottingham, Leicester, UK
| | - Sundus Malaikah
- National Centre for Sport and Exercise Medicine, School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, UK.,NIHR Leicester Biomedical Research Centre, University Hospitals of Leicester NHS Trust and University of Leicester, Leicester, UK.,Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Jack A Sargeant
- NIHR Leicester Biomedical Research Centre, University Hospitals of Leicester NHS Trust and University of Leicester, Leicester, UK.,Diabetes Research Centre, University of Leicester, Leicester, UK
| | - David J Stensel
- National Centre for Sport and Exercise Medicine, School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, UK.,NIHR Leicester Biomedical Research Centre, University Hospitals of Leicester NHS Trust and University of Leicester, Leicester, UK
| | - Guruprasad P Aithal
- NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and the University of Nottingham, Leicester, UK.,Nottingham Digestive Diseases Centre, School of Medicine, University of Nottingham, Nottingham, UK
| | - James A King
- National Centre for Sport and Exercise Medicine, School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, UK.,NIHR Leicester Biomedical Research Centre, University Hospitals of Leicester NHS Trust and University of Leicester, Leicester, UK
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26
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Parhofer KG. Oral Lipid-Lowering Treatments Beyond Statins: Too Old and Outdated or Still Useful? Curr Atheroscler Rep 2021; 23:74. [PMID: 34648074 PMCID: PMC8516754 DOI: 10.1007/s11883-021-00971-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/05/2021] [Indexed: 11/26/2022]
Abstract
Purpose of Review For many years, the lipid-lowering armamentarium consisted of statins and/or ezetimibe and/or bile acid sequestrants and/or fibrates. Now, with the availability of new drugs mostly injectables, the field has changed and the role of oral non-statin drugs (including bempedoic acid) must be reevaluated. Recent Findings Ezetimibe remains a very important combination partner for statins with continuously increasing treatment numbers. Bempedoic acid is another interesting combination partner for statin/ezetimibe or ezetimibe alone but lacks in contrast to ezetimibe evidence from outcome trials. The role of fibrates is less clear as they have shown disappointing results in outcome trials but may still be used in selected, high-risk patients with combined dyslipidemia. Bile acid sequestrants are now rarely used as there are stronger, better tolerable ways to lower LDL-cholesterol. Summary With the introduction of new injectable lipid-lowering drugs, some oral drugs such as ezetimibe and bempedoic acid still have an important spot in our treatment algorithm others such as fibrates have a less clear role while again others are now rarely used.
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Affiliation(s)
- Klaus G Parhofer
- Medizinische Klinik Und Poliklinik IV, LMU Klinikum, Marchioninistr. 15, 81377, Munich, Germany.
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27
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Pellicori P, Vaduganathan M, Ferreira JP, Zannad F, Sanyal AJ. Cross-talk between non-alcoholic fatty liver disease and cardiovascular disease: Implications for future trial design. DIABETES & METABOLISM 2021; 48:101281. [PMID: 34543735 DOI: 10.1016/j.diabet.2021.101281] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 08/30/2021] [Accepted: 09/04/2021] [Indexed: 02/07/2023]
Abstract
The natural history of non-alcoholic fatty liver disease (NAFLD) is still not fully elucidated. Patients with NAFLD have a low risk of liver complications, unless substantial liver fibrosis has developed. On the other hand, NAFLD has been linked with excess metabolic and cardiovascular complications. Therapies targeting common pathways may benefit both NAFLD and underlying cardiometabolic risk. Therefore, there is a rationale for considering cardiovascular endpoints in the context of NAFLD trials and, vice-versa, to consider the concomitant presence of NAFLD in drug development for cardiometabolic disorders. This manuscript provides a framework for consideration for future trials examining the inter-relationship between cardiovascular disease and NAFLD.
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Affiliation(s)
- Pierpaolo Pellicori
- Robertson Institute of Biostatistics and Clinical Trials Unit, University of Glasgow, University Avenue, Glasgow, G12 8QQ.
| | - Muthiah Vaduganathan
- Division of Cardiovascular Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA
| | - João Pedro Ferreira
- Centre d'Investigation Clinique Plurithématique Pierre Drouin-INSERM CHU de Nancy, Nancy, France & Université de Lorraine, FCRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists) Network, France; Cardiovascular R&D Centre (UnIC), Faculty of Medicine, University of Porto, Porto, Portugal
| | - Faiez Zannad
- Centre d'Investigation Clinique Plurithématique Pierre Drouin-INSERM CHU de Nancy, Nancy, France & Université de Lorraine, FCRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists) Network, France
| | - Arun J Sanyal
- Dept. of Internal medicine, Virginia Commonwealth University School of Medicine, Richmond, VA 23298
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28
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Horn CL, Morales AL, Savard C, Farrell GC, Ioannou GN. Role of Cholesterol-Associated Steatohepatitis in the Development of NASH. Hepatol Commun 2021; 6:12-35. [PMID: 34558856 PMCID: PMC8710790 DOI: 10.1002/hep4.1801] [Citation(s) in RCA: 127] [Impact Index Per Article: 31.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Revised: 07/08/2021] [Accepted: 07/14/2021] [Indexed: 12/11/2022] Open
Abstract
The rising prevalence of nonalcoholic fatty liver disease (NAFLD) and NAFLD-related cirrhosis in the United States and globally highlights the need to better understand the mechanisms causing progression of hepatic steatosis to fibrosing steatohepatitis and cirrhosis in a small proportion of patients with NAFLD. Accumulating evidence suggests that lipotoxicity mediated by hepatic free cholesterol (FC) overload is a mechanistic driver for necroinflammation and fibrosis, characteristic of nonalcoholic steatohepatitis (NASH), in many animal models and also in some patients with NASH. Diet, lifestyle, obesity, key genetic polymorphisms, and hyperinsulinemia secondary to insulin resistance are pivotal drivers leading to aberrant cholesterol signaling, which leads to accumulation of FC within hepatocytes. FC overload in hepatocytes can lead to ER stress, mitochondrial dysfunction, development of toxic oxysterols, and cholesterol crystallization in lipid droplets, which in turn lead to hepatocyte apoptosis, necrosis, or pyroptosis. Activation of Kupffer cells and hepatic stellate cells by hepatocyte signaling and cholesterol loading contributes to this inflammation and leads to hepatic fibrosis. Cholesterol accumulation in hepatocytes can be readily prevented or reversed by statins. Observational studies suggest that use of statins in NASH not only decreases the substantially increased cardiovascular risk, but may ameliorate liver pathology. Conclusion: Hepatic FC loading may result in cholesterol-associated steatohepatitis and play an important role in the development and progression of NASH. Statins appear to provide significant benefit in preventing progression to NASH and NASH-cirrhosis. Randomized controlled trials are needed to demonstrate whether statins or statin/ezetimibe combination can effectively reverse steatohepatitis and liver fibrosis in patients with NASH.
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Affiliation(s)
- Christian L Horn
- Division of Gastroenterology and Hepatology, Department of Medicine, San Antonio Military Medical Center, Fort Sam Houston, TX, USA
| | - Amilcar L Morales
- Division of Gastroenterology and Hepatology, Department of Medicine, San Antonio Military Medical Center, Fort Sam Houston, TX, USA
| | - Christopher Savard
- Division of Gastroenterology, Department of Medicine, Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA.,Division of Gastroenterology, Department of Medicine, University of Washington, Seattle, WA, USA.,Research and Development, Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA
| | - Geoffrey C Farrell
- Liver Research Group, ANU Medical School, Australian National University at the Canberra Hospital, Garran, ACT, Australia
| | - George N Ioannou
- Division of Gastroenterology, Department of Medicine, Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA.,Division of Gastroenterology, Department of Medicine, University of Washington, Seattle, WA, USA.,Research and Development, Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA
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29
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Guerra JVS, Dias MMG, Brilhante AJVC, Terra MF, García-Arévalo M, Figueira ACM. Multifactorial Basis and Therapeutic Strategies in Metabolism-Related Diseases. Nutrients 2021; 13:nu13082830. [PMID: 34444990 PMCID: PMC8398524 DOI: 10.3390/nu13082830] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Revised: 08/09/2021] [Accepted: 08/11/2021] [Indexed: 12/11/2022] Open
Abstract
Throughout the 20th and 21st centuries, the incidence of non-communicable diseases (NCDs), also known as chronic diseases, has been increasing worldwide. Changes in dietary and physical activity patterns, along with genetic conditions, are the main factors that modulate the metabolism of individuals, leading to the development of NCDs. Obesity, diabetes, metabolic associated fatty liver disease (MAFLD), and cardiovascular diseases (CVDs) are classified in this group of chronic diseases. Therefore, understanding the underlying molecular mechanisms of these diseases leads us to develop more accurate and effective treatments to reduce or mitigate their prevalence in the population. Given the global relevance of NCDs and ongoing research progress, this article reviews the current understanding about NCDs and their related risk factors, with a focus on obesity, diabetes, MAFLD, and CVDs, summarizing the knowledge about their pathophysiology and highlighting the currently available and emerging therapeutic strategies, especially pharmacological interventions. All of these diseases play an important role in the contamination by the SARS-CoV-2 virus, as well as in the progression and severity of the symptoms of the coronavirus disease 2019 (COVID-19). Therefore, we briefly explore the relationship between NCDs and COVID-19.
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Affiliation(s)
- João V. S. Guerra
- Brazilian Center for Research in Energy and Materials (CNPEM), Brazilian Biosciences National Laboratory (LNBio), Polo II de Alta Tecnologia—R. Giuseppe Máximo Scolfaro, Campinas 13083-100, Brazil; (J.V.S.G.); (M.M.G.D.); (M.F.T.)
- Graduate Program in Pharmaceutical Sciences, Faculty Pharmaceutical Sciences, University of Campinas, Campinas 13083-970, Brazil
| | - Marieli M. G. Dias
- Brazilian Center for Research in Energy and Materials (CNPEM), Brazilian Biosciences National Laboratory (LNBio), Polo II de Alta Tecnologia—R. Giuseppe Máximo Scolfaro, Campinas 13083-100, Brazil; (J.V.S.G.); (M.M.G.D.); (M.F.T.)
- Graduate Program in Functional and Molecular Biology, Institute of Biology, State University of Campinas (Unicamp), Campinas 13083-970, Brazil;
| | - Anna J. V. C. Brilhante
- Graduate Program in Functional and Molecular Biology, Institute of Biology, State University of Campinas (Unicamp), Campinas 13083-970, Brazil;
- Brazilian Center for Research in Energy and Materials (CNPEM), Brazilian Biorenewables National Laboratory (LNBR), Polo II de Alta Tecnologia—R. Giuseppe Máximo Scolfaro, Campinas 13083-100, Brazil
| | - Maiara F. Terra
- Brazilian Center for Research in Energy and Materials (CNPEM), Brazilian Biosciences National Laboratory (LNBio), Polo II de Alta Tecnologia—R. Giuseppe Máximo Scolfaro, Campinas 13083-100, Brazil; (J.V.S.G.); (M.M.G.D.); (M.F.T.)
- Graduate Program in Functional and Molecular Biology, Institute of Biology, State University of Campinas (Unicamp), Campinas 13083-970, Brazil;
| | - Marta García-Arévalo
- Brazilian Center for Research in Energy and Materials (CNPEM), Brazilian Biosciences National Laboratory (LNBio), Polo II de Alta Tecnologia—R. Giuseppe Máximo Scolfaro, Campinas 13083-100, Brazil; (J.V.S.G.); (M.M.G.D.); (M.F.T.)
- Correspondence: or (M.G.-A.); (A.C.M.F.)
| | - Ana Carolina M. Figueira
- Brazilian Center for Research in Energy and Materials (CNPEM), Brazilian Biosciences National Laboratory (LNBio), Polo II de Alta Tecnologia—R. Giuseppe Máximo Scolfaro, Campinas 13083-100, Brazil; (J.V.S.G.); (M.M.G.D.); (M.F.T.)
- Correspondence: or (M.G.-A.); (A.C.M.F.)
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30
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Abstract
PURPOSE OF REVIEW To summarize recent evidence demonstrating increased cardiovascular disease (CVD) risk, and how CVD risk may be reduced, in patients with nonalcoholic fatty liver disease (NAFLD). RECENT FINDINGS NAFLD is a multisystem disease, defined by a spectrum of liver fat-associated conditions extending from simple steatosis, to inflammation, fibrosis and cirrhosis. NAFLD not only increases the risk of liver morbidity and mortality but also increases the risk of CVD morbidity and mortality and is associated with recognized CVD risk factors such as hypertension, atherogenic dyslipidaemia, type 2 diabetes mellitus and chronic kidney disease. Evidence suggests that the liver fibrosis stage may be a strong CVD risk factor. Lifestyle measures (e.g. weight loss and increased physical activity) are effective in improving CVD risk factors. Hypoglycaemic agents, such as the peroxisome proliferator-activated receptor gamma agonist pioglitazone and the glucagon-like peptide-1 receptor agonist liraglutide, reduce cardiovascular risk and may improve liver histology. Statin and antihypertensive treatments are well tolerated and currently it is unclear whether novel antifibrotic drugs will reduce CVD risk. SUMMARY Assessment and treatment of increased cardiovascular risk is important in patients with NAFLD. If not contra-indicated, pioglitazone or a glucagon-like peptide 1 agonist should be considered and may benefit both CVD risk and early liver disease.
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Affiliation(s)
- Michael P Johnston
- Department of Gastroenterology, Glasgow Royal Infirmary, Glasgow, Scotland
| | - Janisha Patel
- Department of Hepatology, University Hospital Southampton
| | - Christopher D Byrne
- Nutrition and Metabolism, Faculty of Medicine, University of Southampton
- National Institute for Health Research Southampton Biomedical Research Centre, University Hospital Southampton, Southampton, UK
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31
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Li H, Yu XH, Ou X, Ouyang XP, Tang CK. Hepatic cholesterol transport and its role in non-alcoholic fatty liver disease and atherosclerosis. Prog Lipid Res 2021; 83:101109. [PMID: 34097928 DOI: 10.1016/j.plipres.2021.101109] [Citation(s) in RCA: 122] [Impact Index Per Article: 30.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 05/31/2021] [Accepted: 06/02/2021] [Indexed: 12/12/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a quickly emerging global health problem representing the most common chronic liver disease in the world. Atherosclerotic cardiovascular disease represents the leading cause of mortality in NAFLD patients. Cholesterol metabolism has a crucial role in the pathogenesis of both NAFLD and atherosclerosis. The liver is the major organ for cholesterol metabolism. Abnormal hepatic cholesterol metabolism not only leads to NAFLD but also drives the development of atherosclerotic dyslipidemia. The cholesterol level in hepatocytes reflects the dynamic balance between endogenous synthesis, uptake, esterification, and export, a process in which cholesterol is converted to neutral cholesteryl esters either for storage in cytosolic lipid droplets or for secretion as a major constituent of plasma lipoproteins, including very-low-density lipoproteins, chylomicrons, high-density lipoproteins, and low-density lipoproteins. In this review, we describe decades of research aimed at identifying key molecules and cellular players involved in each main aspect of hepatic cholesterol metabolism. Furthermore, we summarize the recent advances regarding the biological processes of hepatic cholesterol transport and its role in NAFLD and atherosclerosis.
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Affiliation(s)
- Heng Li
- Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang Medical College, University of South China, Hengyang, Hunan 421001, China
| | - Xiao-Hua Yu
- Institute of Clinical Medicine, The Second Affiliated Hospital of Hainan Medical University, Haikou, Hainan 460106, China
| | - Xiang Ou
- Department of Endocrinology, the First Hospital of Changsha, Changsha, Hunan 410005, China
| | - Xin-Ping Ouyang
- Department of Physiology, Institute of Neuroscience Research, Hengyang Key Laboratory of Neurodegeneration and Cognitive Impairment, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang Medical College, University of South China, Hengyang, Hunan 421001, China.
| | - Chao-Ke Tang
- Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang Medical College, University of South China, Hengyang, Hunan 421001, China.
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Ahadi M, Molooghi K, Masoudifar N, Namdar AB, Vossoughinia H, Farzanehfar M. A review of non-alcoholic fatty liver disease in non-obese and lean individuals. J Gastroenterol Hepatol 2021; 36:1497-1507. [PMID: 33217052 DOI: 10.1111/jgh.15353] [Citation(s) in RCA: 56] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2020] [Revised: 10/26/2020] [Accepted: 11/10/2020] [Indexed: 12/12/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is one of the most common causes of hepatic disorders. It represents a wide range of chronic liver diseases in patients with no history of significant alcohol consumption, starting with simple steatosis and progressing towards non-alcoholic steatohepatitis, cirrhosis, and ultimately hepatocellular carcinoma. NAFLD is usually associated with type 2 diabetes mellitus, dyslipidemia, metabolic syndrome, and obesity. This disease has mostly been studied in obese individuals; however, it has been widely reported and studied among the lean/non-obese population in recent years. The pathogenesis of NAFLD in non-obese patients is associated with various genetic predispositions, particularly a patatin-like phospholipase domain-containing protein 3 G allele polymorphism, which results in the accumulation of triglyceride in the liver and resistance to insulin. Additionally, dietary factors such as high fructose consumption seem to play a substantial role in the pathology of non-obese NAFLD. Although there is not enough evidence on the treatment of NAFLD in non-obese patients, the standard approach is to advise altering one's lifestyle in order to diminish visceral adiposity. Dietary modification, weight loss, and increased physical activity are highly recommended. We aimed to review and summarize the existing information on the prevalence, pathogenesis, genetic predispositions, diagnosis, and treatment of NAFLD in non-obese patients according to the latest literature.
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Affiliation(s)
- Mitra Ahadi
- Department of Gastroenterology and Hepatology, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Kasra Molooghi
- School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Negin Masoudifar
- School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ali Beheshti Namdar
- Department of Gastroenterology and Hepatology, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hassan Vossoughinia
- Department of Gastroenterology and Hepatology, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammadreza Farzanehfar
- Department of Gastroenterology and Hepatology, Mashhad University of Medical Sciences, Mashhad, Iran
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Mahmoudi L, Asadi S, Al-Mousavi Z, Niknam R. A randomized controlled clinical trial comparing calcitriol versus cholecalciferol supplementation to reduce insulin resistance in patients with non-alcoholic fatty liver disease. Clin Nutr 2021; 40:2999-3005. [PMID: 33341312 DOI: 10.1016/j.clnu.2020.11.037] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Revised: 11/17/2020] [Accepted: 11/27/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in the world with no definite treatment. Insulin resistance (IR) and low serum vitamin D are closely linked to NAFLD. Since there is no comparative study on the effect of calcitriol with cholecalciferol on NAFLD based on homeostasis model of insulin resistance (HOMA-IR) as an IR indicator, so we designed this research. METHODS A double blind randomized clinical trial was conducted on patients with NAFLD with concomitant vitamin D deficiency/insufficiency at two referral tertiary teaching medical centers, from July 2017 to January 2019. Patients were randomly divided into two groups: calcitriol (1 mcg/day) and cholecalciferol (50,000 IU/week) for 8 weeks. Before and after the intervention, anthropometric and laboratory data were measured and HOMA-IR was calculated for each patient. RESULTS 54 patients completed the trial. In total, calcitriol supplementation improved serum insulin levels as well as IR based on the HOMA-IR index, significantly compared to the cholecalciferol group. HOMA-IR decreased 1.8 times more in patients receiving calcitriol than in those receiving cholecalciferol, which was clinically meaningful. The observed changes were more pronounced in patients with higher baseline body mass index. Moreover, calcitriol was more associated with a significant decrease in liver enzymes and cholesterol levels comparing to cholecalciferol. CONCLUSION Based on the findings of this study, the use of calcitriol supplementation significantly reduced HOMA-IR as an IR indicator in NAFLD patients, compared to cholecalciferol. To confirm this findings, further studies with larger sample sizes are recommended.
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Affiliation(s)
- Laleh Mahmoudi
- Department of Clinical Pharmacy, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Sara Asadi
- Department of Clinical Pharmacy, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Zahra Al-Mousavi
- Department of Clinical Pharmacy, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Ramin Niknam
- Department of Internal Medicine, School of Medicine, Gastroenterohepatology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
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Zhu X, Wu M, Wang H, Li H, Lin J, Peng Y, Hu Y, Li C, Ding Y. Safety, tolerability, and pharmacokinetics of the novel pan-phosphodiesterase inhibitor ZSP1601 in healthy subjects: a double-blinded, placebo-controlled first-in-human single-dose and multiple-dose escalation and food effect study. Expert Opin Investig Drugs 2021; 30:579-589. [PMID: 33682556 DOI: 10.1080/13543784.2021.1900822] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Background: The pharmacokinetics (PK), safety, and tolerability profiles of ZSP1601, a first-in-class pan-phosphodiesterase (PDE) inhibitor, were evaluated in healthy Chinese volunteers.Research design and methods: This Phase 1a study consisted of a double-blinded, randomized, placebo-controlled single ascending dose (SAD) (25 to 350 mg), multiple ascending doses (MAD) (50 or 100 mg QD), and a two-period crossover food effect study (100 mg).Results: ZSP1601 was quickly absorbed, with maximum plasma concentrations (Cmax) reached at 1.25 to 2.50 h (median Tmax). The exposures exhibited dose-proportional increases, while the mean half-life (t1/2) ranged from 6.34-8.64 h. Steady-state was reached within seven days in the MAD study. The mean steady trough concentrations were 423 and 588 ng/mL, respectively. ZSP1601 accumulation was low, with ratios ≤ 1.5. The bioavailability of ZSP1601 was equivalent under fasted and fed states. All adverse events (AEs) were assessed as mild or moderate, with headaches as the most common. The highest single doses (275 and 350 mg) yielded more AEs, yet the rates were similar with the placebo cohorts in the MAD study.Conclusions: The safety and PK profiles of ZSP1601 support further efficacy evaluation in nonalcoholic steatohepatitis patients.Trial registration: The trial is registered at ClinicalTrials.gov (CT.gov identifier: NCT03392779).
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Affiliation(s)
- Xiaoxue Zhu
- Phase I Clinical Trial Unit, First Hospital, Jilin University, Changchun, China
| | - Min Wu
- Phase I Clinical Trial Unit, First Hospital, Jilin University, Changchun, China
| | - Hong Wang
- Jilin Medical Products Administration, Changchun, China
| | - Haijun Li
- Medical Affairs, Guangdong Raynovent Biotech Co., Ltd, Shenzhen, China
| | - Junjie Lin
- Medical Affairs, Guangdong Raynovent Biotech Co., Ltd, Shenzhen, China
| | - Yun Peng
- Medical Affairs, Guangdong Zhongsheng Pharmaceutical Co., Ltd, Dongguan, China
| | - Yue Hu
- Phase I Clinical Trial Unit, First Hospital, Jilin University, Changchun, China
| | - Cuiyun Li
- Phase I Clinical Trial Unit, First Hospital, Jilin University, Changchun, China
| | - Yanhua Ding
- Phase I Clinical Trial Unit, First Hospital, Jilin University, Changchun, China
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Kim JY, He F, Karin M. From Liver Fat to Cancer: Perils of the Western Diet. Cancers (Basel) 2021; 13:1095. [PMID: 33806428 PMCID: PMC7961422 DOI: 10.3390/cancers13051095] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Revised: 02/27/2021] [Accepted: 02/28/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC), the most common type of primary liver cancer provides the prototypical example of an obesity-related cancer. The obesity epidemic gave rise to an enormous increase in the incidence of non-alcoholic fatty liver disease (NAFLD), a condition that affects one third of American adults. In about 20% of these individuals, simple liver steatosis (hepatosteatosis) progresses to non-alcoholic steatohepatitis (NASH) characterized by chronic liver injury, inflammation, and fibrosis. In addition to liver failure, NASH greatly increases the risk of HCC. Here we discuss the metabolic processes that control the progression from NAFLD to NASH and from NASH to HCC, with a special emphasis on the role of free-non-esterified cholesterol in the process.
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Affiliation(s)
- Ju Youn Kim
- Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, University of California San Diego, 9500 Gilman Drive, San Diego, CA 92093, USA;
| | - Feng He
- Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai 201203, China;
| | - Michael Karin
- Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, University of California San Diego, 9500 Gilman Drive, San Diego, CA 92093, USA;
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Mantovani A, Dalbeni A. Treatments for NAFLD: State of Art. Int J Mol Sci 2021; 22:ijms22052350. [PMID: 33652942 PMCID: PMC7956331 DOI: 10.3390/ijms22052350] [Citation(s) in RCA: 142] [Impact Index Per Article: 35.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Revised: 02/22/2021] [Accepted: 02/23/2021] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is to date the most common chronic liver disease in clinical practice and, consequently, a major health problem worldwide. It affects approximately 30% of adults in the general population and up to 70% of patients with type 2 diabetes (T2DM). Despite the current knowledge of the epidemiology, pathogenesis, and natural history of NAFLD, no specific pharmacological therapies are until now approved for this disease and, consequently, general strategies have been proposed to manage it. They include: (a) lifestyle change in order to promote weight loss by diet and physical activity, (b) control of the main cardiometabolic risk factors, (c) correction of all modifiable risk factors leading the development and progression of advanced forms of NAFLD, and (d) prevention of hepatic and extra-hepatic complications. In the last decade, several potential agents have been widely investigated for the treatment of NAFLD and its advanced forms—shedding some light but casting a few shadows. They include some glucose-lowering drugs (such as pioglitazone, glucagon-like peptide-1 (GLP-1) receptor agonists, sodium-glucose co-transporter-2 (SGLT-2) inhibitors), antioxidants (such as vitamin E), statins or other lipid lowering agents, bile and non-bile acid farnesoid X activated receptor (FXR) agonists, and others. This narrative review discusses in detail the different available approaches with the potential to prevent and treat NAFLD and its advanced forms.
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Affiliation(s)
- Alessandro Mantovani
- Section of Endocrinology, Diabetes and Metabolism, University and Azienda Ospedaliera Universitaria Integrata of Verona, 37126 Verona, Italy
- Correspondence:
| | - Andrea Dalbeni
- Section of General Medicine, Hypertension and Liver Unit, University and Azienda Ospedaliera Universitaria Integrata of Verona, 37134 Verona, Italy;
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Zhang H, Léveillé M, Courty E, Gunes A, N Nguyen B, Estall JL. Differences in metabolic and liver pathobiology induced by two dietary mouse models of nonalcoholic fatty liver disease. Am J Physiol Endocrinol Metab 2020; 319:E863-E876. [PMID: 32924526 DOI: 10.1152/ajpendo.00321.2020] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a growing epidemic linked to metabolic disease. The first stage of NAFLD is characterized by lipid accumulation in hepatocytes, but this can progress into nonalcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma (HCC). Western diets, high in fats, sugars, and cholesterol, are linked to NAFLD development. Murine models are often used to study NAFLD; however, there remains debate on which diet-induced model best mimics both human disease progression and pathogenesis. In this study, we performed a side-by-side comparison of two popular diet models of murine NAFLD/NASH and associated HCC, a high-fat diet supplemented with 30% fructose water (HFHF) and a Western diet high in cholesterol (WDHC), and these were compared with a common grain-based chow diet (GBD). Mice on both experimental diets developed liver steatosis, and WDHC-fed mice had greater levels of hepatic inflammation and fibrosis than HFHF-fed mice. In contrast, HFHF-fed mice were more obese and developed more severe metabolic syndrome, with less pronounced liver disease. Despite these differences, WDHC-fed and HFHF-fed mice had similar tumor burdens in a model of diet-potentiated liver cancer. Response to diet and resulting phenotypes were generally similar between sexes, albeit delayed in females. This study shows that modest differences in diet can significantly uncouple glucose homeostasis and liver damage. In conclusion, long-term feeding of either HFHF or WDHC is a reliable method to induce NASH and diet-potentiated liver cancer in mice of both sexes; however, the choice of diet involves a trade-off between severity of metabolic syndrome and liver damage.
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Affiliation(s)
- Hannah Zhang
- Institut de recherches cliniques de Montréal (IRCM), Montreal, Quebec, Canada
- Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec, Canada
| | - Mélissa Léveillé
- Institut de recherches cliniques de Montréal (IRCM), Montreal, Quebec, Canada
- Department of Medicine, University of Montreal, Montreal, Quebec, Canada
| | - Emilie Courty
- Institut de recherches cliniques de Montréal (IRCM), Montreal, Quebec, Canada
- Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada
| | - Aysim Gunes
- Institut de recherches cliniques de Montréal (IRCM), Montreal, Quebec, Canada
- Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada
| | - Bich N Nguyen
- Department of Pathology and Cell Biology, University of Montreal, Montreal, Quebec, Canada
- University of Montreal Health Network (CHUM), Montreal, Quebec Canada
| | - Jennifer L Estall
- Institut de recherches cliniques de Montréal (IRCM), Montreal, Quebec, Canada
- Department of Medicine, University of Montreal, Montreal, Quebec, Canada
- Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec, Canada
- Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada
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Arab JP, Dirchwolf M, Álvares-da-Silva MR, Barrera F, Benítez C, Castellanos-Fernandez M, Castro-Narro G, Chavez-Tapia N, Chiodi D, Cotrim H, Cusi K, de Oliveira CPMS, Díaz J, Fassio E, Gerona S, Girala M, Hernandez N, Marciano S, Masson W, Méndez-Sánchez N, Leite N, Lozano A, Padilla M, Panduro A, Paraná R, Parise E, Perez M, Poniachik J, Restrepo JC, Ruf A, Silva M, Tagle M, Tapias M, Torres K, Vilar-Gomez E, Costa Gil JE, Gadano A, Arrese M. Latin American Association for the study of the liver (ALEH) practice guidance for the diagnosis and treatment of non-alcoholic fatty liver disease. Ann Hepatol 2020; 19:674-690. [PMID: 33031970 DOI: 10.1016/j.aohep.2020.09.006] [Citation(s) in RCA: 87] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Accepted: 09/17/2020] [Indexed: 02/07/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) currently represents an epidemic worldwide. NAFLD is the most frequently diagnosed chronic liver disease, affecting 20-30% of the general population. Furthermore, its prevalence is predicted to increase exponentially in the next decades, concomitantly with the global epidemic of obesity, type 2 diabetes mellitus (T2DM), and sedentary lifestyle. NAFLD is a clinical syndrome that encompasses a wide spectrum of associated diseases and hepatic complications such as hepatocellular carcinoma (HCC). Moreover, this disease is believed to become the main indication for liver transplantation in the near future. Since NAFLD management represents a growing challenge for primary care physicians, the Asociación Latinoamericana para el Estudio del Hígado (ALEH) has decided to organize this Practice Guidance for the Diagnosis and Treatment of Non-Alcoholic Fatty Liver Disease, written by Latin-American specialists in different clinical areas, and destined to general practitioners, internal medicine specialists, endocrinologists, diabetologists, gastroenterologists, and hepatologists. The main purpose of this document is to improve patient care and awareness of NAFLD. The information provided in this guidance may also be useful in assisting stakeholders in the decision-making process related to NAFLD. Since new evidence is constantly emerging on different aspects of the disease, updates to this guideline will be required in future.
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Affiliation(s)
- Juan Pablo Arab
- Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.
| | - Melisa Dirchwolf
- Unidad de Trasplante Hepático, Servicio de Hepatología, Hospital Privado de Rosario, Rosario, Argentina.
| | - Mário Reis Álvares-da-Silva
- Hepatology Division, Hospital de Clinicas de Porto Alegre, Brazil; School of Medicine, Universidade Federal do Rio Grande do Sul, Brazil; Graduate Program in Gastroenterology and Hepatology, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
| | - Francisco Barrera
- Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.
| | - Carlos Benítez
- Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.
| | | | - Graciela Castro-Narro
- Gastroenterology Department, National Institute of Medical Sciences and Nutrition "Salvador Zubirán", Mexico City, Mexico.
| | | | - Daniela Chiodi
- Hospital de Clínicas, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay.
| | - Helma Cotrim
- School of Medicine, Federal University of Bahia, Salvador, Bahia, Brazil.
| | - Kenneth Cusi
- Division of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, FL, USA.
| | | | - Javier Díaz
- Departamento del Aparato Digestivo, Hospital Edgardo Rebagliati Martins, EsSalud, Lima, Peru.
| | - Eduardo Fassio
- Sección Hígado, Vías Biliares y Páncreas, Servicio de Gastroenterología, Hospital Nacional Profesor Alejandro Posadas, El Palomar, Buenos Aires, Argentina.
| | - Solange Gerona
- Liver Unit, Hospital de Fuerzas Armadas, Montevideo, Uruguay.
| | | | - Nelia Hernandez
- Hospital de Clínicas, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay.
| | | | - Walter Masson
- Hospital Italiano de Buenos Aires, Buenos Aires, Argentina.
| | | | - Nathalie Leite
- School of Medicine, Internal Medicine Department and Clementino Fraga Filho University Hospital, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
| | - Adelina Lozano
- Unidad de Hígado, Servicio de Gastroenterología, Hospital Nacional Arzobispo Loayza, Lima, Peru; Universidad Peruana Cayetano Heredia, Lima, Peru.
| | | | - Arturo Panduro
- Department of Molecular Biology in Medicine, Civil Hospital of Guadalajara, Fray Antonio Alcalde, Guadalajara, Jalisco, Mexico.
| | - Raymundo Paraná
- School of Medicine, Federal University of Bahia, Salvador, Bahia, Brazil.
| | - Edison Parise
- Department of Gastroenterology, Federal University of Sao Paulo, Sao Paulo, Brazil.
| | - Marlene Perez
- Hospital General de la Plaza de la Salud, Santo Domingo, Dominican Republic.
| | - Jaime Poniachik
- Sección de Gastroenterología, Hospital Clínico Universidad de Chile, Santiago, Chile.
| | - Juan Carlos Restrepo
- Hepatobiliary and Liver Transplant Program, Hospital Pablo Tobon Uribe-Universidad de Antioquia, Medellín, Colombia; Grupo Gastrohepatologia, Facultad de Medicina, Universidad of Antioquía UdeA, Medellin, Colombia.
| | - Andrés Ruf
- Unidad de Trasplante Hepático, Servicio de Hepatología, Hospital Privado de Rosario, Rosario, Argentina.
| | - Marcelo Silva
- Hepatology and Liver Transplant Unit, Hospital Universitario Austral, Pilar, Argentina.
| | - Martín Tagle
- Facultad de Medicina Alberto Hurtado, Universidad Peruana Cayetano Heredia, Lima, Peru.
| | - Monica Tapias
- Hospital Universitario Fundación Santa Fe de Bogotá, Bogotá, Colombia.
| | - Kenia Torres
- Hospital General de la Plaza de la Salud, Santo Domingo, Dominican Republic.
| | - Eduardo Vilar-Gomez
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, IN, USA.
| | | | - Adrian Gadano
- Liver Unit, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina.
| | - Marco Arrese
- Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.
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Arslan U, Yenerçağ M. Relationship between non-alcoholic fatty liver disease and coronary heart disease. World J Clin Cases 2020; 8:4688-4699. [PMID: 33195636 PMCID: PMC7642538 DOI: 10.12998/wjcc.v8.i20.4688] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Revised: 09/17/2020] [Accepted: 09/25/2020] [Indexed: 02/05/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease and considered a liver manifestation of metabolic syndrome. It is in close relationship with insulin resistance, obesity, diabetes mellitus, all of which increase risk of cardiovascular disease (CVD). Besides, many studies point out that NAFLD independently contributes to the development of atherosclerosis and CHD. On the other hand, CVDs are the leading cause of death in NAFLD patients. Many pathophysiological changes and molecular mechanisms play an important role in NAFLD for CVD formation. Atherosclerosis is common in NAFLD, which also mainly contributes to the CVD formation and CHD. Many studies linking atherosclerotic CHD and NAFLD are present in the literature. Subclinical CHD, mainly detected by coronary computed tomography views, have been detected more common in NAFLD patients. Presence of NAFLD has been found to be more common in patients with severe CHD and in stable CHD, NAFLD has been found to be associated with more diffuse disease. In acute coronary syndromes, especially in acute myocardial infarction, patients with NAFLD have been found to have poor prognosis when compared with NAFLD free patients. In this review, our aim is to evaluate the relationship between NAFLD and CHD in detail and go over the pathophysiological mechanisms underlying this relationship.
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Affiliation(s)
- Ugur Arslan
- Department of Cardiology, University of Health Sciences Samsun Training and Research Hospital, Samsun 55400, Turkey
| | - Mustafa Yenerçağ
- Department of Cardiology, University of Health Sciences Samsun Training and Research Hospital, Samsun 55400, Turkey
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Sinha RA, Rajak S, Singh BK, Yen PM. Hepatic Lipid Catabolism via PPARα-Lysosomal Crosstalk. Int J Mol Sci 2020; 21:2391. [PMID: 32244266 PMCID: PMC7170715 DOI: 10.3390/ijms21072391] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Revised: 03/01/2020] [Accepted: 03/02/2020] [Indexed: 12/13/2022] Open
Abstract
Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors which belong to the nuclear hormone receptor superfamily. They regulate key aspects of energy metabolism within cells. Recently, PPARα has been implicated in the regulation of autophagy-lysosomal function, which plays a key role in cellular energy metabolism. PPARα transcriptionally upregulates several genes involved in the autophagy-lysosomal degradative pathway that participates in lipolysis of triglycerides within the hepatocytes. Interestingly, a reciprocal regulation of PPARα nuclear action by autophagy-lysosomal activity also exists with implications in lipid metabolism. This review succinctly discusses the unique relationship between PPARα nuclear action and lysosomal activity and explores its impact on hepatic lipid homeostasis under pathological conditions such as non-alcoholic fatty liver disease (NAFLD).
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Affiliation(s)
- Rohit A. Sinha
- Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India;
| | - Sangam Rajak
- Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India;
| | - Brijesh K. Singh
- Program of Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, 8 College Road, Singapore 169587, Singapore (P.M.Y.)
| | - Paul M. Yen
- Program of Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, 8 College Road, Singapore 169587, Singapore (P.M.Y.)
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Grefhorst A, van de Peppel IP, Larsen LE, Jonker JW, Holleboom AG. The Role of Lipophagy in the Development and Treatment of Non-Alcoholic Fatty Liver Disease. Front Endocrinol (Lausanne) 2020; 11:601627. [PMID: 33597924 PMCID: PMC7883485 DOI: 10.3389/fendo.2020.601627] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Accepted: 12/14/2020] [Indexed: 12/13/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) or metabolic (dysfunction) associated liver disease (MAFLD), is, with a global prevalence of 25%, the most common liver disorder worldwide. NAFLD comprises a spectrum of liver disorders ranging from simple steatosis to steatohepatitis, fibrosis, cirrhosis and eventually end-stage liver disease. The cause of NAFLD is multifactorial with genetic susceptibility and an unhealthy lifestyle playing a crucial role in its development. Disrupted hepatic lipid homeostasis resulting in hepatic triglyceride accumulation is an hallmark of NAFLD. This disruption is commonly described based on four pathways concerning 1) increased fatty acid influx, 2) increased de novo lipogenesis, 3) reduced triglyceride secretion, and 4) reduced fatty acid oxidation. More recently, lipophagy has also emerged as pathway affecting NAFLD development and progression. Lipophagy is a form of autophagy (i.e. controlled autolysosomal degradation and recycling of cellular components), that controls the breakdown of lipid droplets in the liver. Here we address the role of hepatic lipid homeostasis in NAFLD and specifically review the current literature on lipophagy, describing its underlying mechanism, its role in pathophysiology and its potential as a therapeutic target.
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Affiliation(s)
- Aldo Grefhorst
- Department of Experimental Vascular Medicine, Amsterdam University Medical Centers, location AMC, Amsterdam, Netherlands
- *Correspondence: Aldo Grefhorst,
| | - Ivo P. van de Peppel
- Section of Molecular Metabolism and Nutrition, Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
| | - Lars E. Larsen
- Department of Experimental Vascular Medicine, Amsterdam University Medical Centers, location AMC, Amsterdam, Netherlands
- Section of Molecular Metabolism and Nutrition, Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
| | - Johan W. Jonker
- Section of Molecular Metabolism and Nutrition, Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
| | - Adriaan G. Holleboom
- Department of Vascular Medicine, Amsterdam University Medical Centers, location AMC, Amsterdam, Netherlands
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42
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Katsiki N, Tousoulis D. Diabetes mellitus and comorbidities: A bad romance. Hellenic J Cardiol 2020; 61:23-25. [PMID: 32454183 DOI: 10.1016/j.hjc.2020.02.009] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Accepted: 02/27/2020] [Indexed: 02/08/2023] Open
Affiliation(s)
- Niki Katsiki
- First Department of Internal Medicine, Diabetes Center, Division of Endocrinology and Metabolism, AHEPA University Hospital, Thessaloniki, Greece.
| | - Dimitrios Tousoulis
- First Department of Cardiology, National and Kapodistrian University of Athens, Hippokrateion Hospital, Athens, Greece
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43
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Shaposhnik II, Genkel VV. [Pleiotropic effects of ezetimibe]. KARDIOLOGIIA 2019; 59:12-17. [PMID: 31995721 DOI: 10.18087/cardio.n875] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/04/2019] [Revised: 11/13/2019] [Accepted: 12/10/2019] [Indexed: 06/10/2023]
Abstract
The article discusses in detail the question of the additional positive effects of ezetimibe in addition to direct hypolipidemic action. The data of experimental and clinical studies in which the effect of ezetimibe on carbohydrate metabolism, inflammation, endothelial dysfunction, and liver is studied. The article also discusses the results of clinical studies that examined the effect of ezetimibe on atherosclerotic plaque.
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Affiliation(s)
- I I Shaposhnik
- Federal State Budgetary Educational Institution of Higher Education "South-Ural State Medical University" of the Ministry of Healthcare of the Russian Federation
| | - V V Genkel
- Federal State Budgetary Educational Institution of Higher Education "South-Ural State Medical University" of the Ministry of Healthcare of the Russian Federation
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44
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Ganguli S, DeLeeuw P, Satapathy SK. A Review Of Current And Upcoming Treatment Modalities In Non-Alcoholic Fatty Liver Disease And Non-Alcoholic Steatohepatitis. Hepat Med 2019; 11:159-178. [PMID: 31814783 PMCID: PMC6863115 DOI: 10.2147/hmer.s188991] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2019] [Accepted: 10/03/2019] [Indexed: 12/15/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the West. Non-alcoholic steatohepatitis (NASH) is the progressive form of NAFLD and can lead to cirrhosis, hepatocellular carcinoma, and is associated with increased cardiovascular risks. Multiple components and risk factors are thought to be involved in the pathogenesis of NAFLD and NASH. Optimal therapy has not yet been found, but many advances have been made with the discovery of potential therapeutic options. In this paper, we aim to provide a comprehensive review of approved, studied, and upcoming treatment options for NAFLD and NASH. Non-pharmacologic therapy (lifestyle modifications and bariatric surgery) and pharmacologic therapy are both reviewed. Pharmacologic therapy target components thought to be involved in the pathogenesis of this disease process including insulin resistance, oxidative stress, inflammation, lipid metabolism, and fibrosis are reviewed in this paper. Results of the emerging treatment targets in phase 2 and 3 clinical trials are also included.
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Affiliation(s)
- Surosree Ganguli
- Division of Internal Medicine, University of Louisville, Louisville, KY40202, USA
| | - Peter DeLeeuw
- Division of Internal Medicine, University of Tennessee Health Science Center, Memphis, TN38163, USA
| | - Sanjaya K Satapathy
- Division of Hepatology and Sandra Atlas Bass Center for Liver Diseases, Northwell Health, Manhasset, NY11030, USA
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45
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Sumida Y, Okanoue T, Nakajima A. Phase 3 drug pipelines in the treatment of non-alcoholic steatohepatitis. Hepatol Res 2019; 49:1256-1262. [PMID: 31495973 DOI: 10.1111/hepr.13425] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2019] [Revised: 08/28/2019] [Accepted: 08/29/2019] [Indexed: 01/09/2023]
Abstract
Non-alcoholic steatohepatitis (NASH), which is a more severe form of non-alcoholic fatty liver disease, can at least partly lead to cirrhosis, hepatocellular carcinoma, and hepatic failure. Liver transplantation is the only option for NASH cirrhosis at this time. By 2020, NASH is projected to overtake hepatitis C as the leading cause of liver transplants in the USA. There are still no approved drugs for treating NASH. Although there are approximately 196 agents of investigational NASH therapies in various stages of development, we here mainly review phase 3 drug candidates in the pipeline for NASH. The NASH space across the seven major markets of the USA, France, Germany, Italy, Spain, the UK, and Japan, is set to rise from $618 million in 2016 to approximately $25.3 billion by 2026. However, the fact that the race to develop an effective drug against NASH has reached the home stretch, with five drug candidates (obeticholic acid, elafibranor, selonsertib, cenicriviroc, and resmetirom) in phase 3 stage of the trial, is welcome news for patients. The very earliest a NASH drug could hit the market is 2021, assuming all goes well as planned.
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Affiliation(s)
- Yoshio Sumida
- Division of Hepatology and Pancreatology, Department of Internal Medicine, Aichi Medical University, Nagakute, Japan
| | | | - Atsushi Nakajima
- Department of Gastroenterology and Hepatology, Yokohama City University, Yokohama, Japan
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Shimozato N, Namisaki T, Kaji K, Kitade M, Okura Y, Sato S, Moriya K, Seki K, Kawaratani H, Takaya H, Sawada Y, Saikawa S, Nakanishi K, Furukawa M, Fujinaga Y, Kubo T, Asada K, Kitagawa K, Tsuji Y, Kaya D, Ozutsumi T, Akahane T, Mitoro A, Yoshiji H. Combined effect of a farnesoid X receptor agonist and dipeptidyl peptidase-4 inhibitor on hepatic fibrosis. Hepatol Res 2019; 49:1147-1161. [PMID: 31177586 DOI: 10.1111/hepr.13385] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2018] [Revised: 05/18/2019] [Accepted: 05/22/2019] [Indexed: 12/11/2022]
Abstract
AIM Non-alcoholic steatohepatitis (NASH) has a broad clinicopathological spectrum (inflammation to severe fibrosis). The farnesoid X receptor agonist obeticholic acid (OCA) ameliorates the histological features of NASH; satisfactory antifibrotic effects have not yet been reported. Here, we investigated the combined effects of OCA + a dipeptidyl peptidase-4 inhibitor (sitagliptin) on hepatic fibrogenesis in a rat model of NASH. METHODS Fifty Fischer 344 rats were fed a choline-deficient L-amino-acid-defined (CDAA) diet for 12 weeks. The in vitro and in vivo effects of OCA + sitagliptin were assessed along with hepatic fibrogenesis, lipopolysaccharide-Toll-like receptor 4 (TLR4) regulatory cascade and intestinal barrier function. Direct inhibitory effects of OCA + sitagliptin on activated hepatic stellate cells (Ac-HSCs) were assessed in vitro. RESULTS Treatment with OCA + sitagliptin potentially inhibited hepatic fibrogenesis along with Ac-HSC proliferation and hepatic transforming growth factor (TGF)-β1, α1(I)-procollagen, and tissue inhibitor of metalloproteinase-1 (TIMP-1) mRNA expression and hydroxyproline levels. Obeticholic acid inhibited hepatic TLR4 expression and increased hepatic matrix metalloproteinase-2 expression. Obeticholic acid decreased intestinal permeability by ameliorating CDAA diet-induced zonula occludens-1 disruption, whereas sitagliptin directly inhibited Ac-HSC proliferation. The in vitro suppressive effects of OCA + sitagliptin on TGF-β1 and α1(I)-procollagen mRNA expression and p38 phosphorylation in Ac-HSCs were almost consistent. Sitagliptin directly inhibited the regulation of Ac-HSC. CONCLUSIONS Treatment with OCA + sitagliptin synergistically affected hepatic fibrogenesis by counteracting endotoxemia induced by intestinal barrier dysfunction and suppressing Ac-HSC proliferation. Thus, OCA + sitagliptin could be a promising therapeutic strategy for NASH.
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Affiliation(s)
- Naotaka Shimozato
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
| | - Tadashi Namisaki
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
| | - Kosuke Kaji
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
| | - Mitsuteru Kitade
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
| | - Yasushi Okura
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
| | - Shinya Sato
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
| | - Kei Moriya
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
| | - Kenichiro Seki
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
| | - Hideto Kawaratani
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
| | - Hiroaki Takaya
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
| | - Yasuhiko Sawada
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
| | - Soichiro Saikawa
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
| | - Keisuke Nakanishi
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
| | - Masanori Furukawa
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
| | - Yukihisa Fujinaga
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
| | - Takuya Kubo
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
| | - Kiyoshi Asada
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
| | - Koh Kitagawa
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
| | - Yuki Tsuji
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
| | - Daisuke Kaya
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
| | - Takahiro Ozutsumi
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
| | - Takemi Akahane
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
| | - Akira Mitoro
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
| | - Hitoshi Yoshiji
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
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Cardiovascular Risk in Non-Alcoholic Fatty Liver Disease: Mechanisms and Therapeutic Implications. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2019; 16:ijerph16173104. [PMID: 31455011 PMCID: PMC6747357 DOI: 10.3390/ijerph16173104] [Citation(s) in RCA: 128] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/16/2019] [Revised: 08/18/2019] [Accepted: 08/21/2019] [Indexed: 02/06/2023]
Abstract
New evidence suggests that non-alcoholic fatty liver disease (NAFLD) has a strong multifaceted relationship with diabetes and metabolic syndrome, and is associated with increased risk of cardiovascular events, regardless of traditional risk factors, such as hypertension, diabetes, dyslipidemia, and obesity. Given the pandemic-level rise of NAFLD—in parallel with the increasing prevalence of obesity and other components of the metabolic syndrome—and its association with poor cardiovascular outcomes, the question of how to manage NAFLD properly, in order to reduce the burden of associated incident cardiovascular events, is both timely and highly relevant. This review aims to summarize the current knowledge of the association between NAFLD and cardiovascular disease, and also to discuss possible clinical strategies for cardiovascular risk assessment, as well as the spectrum of available therapeutic strategies for the prevention and treatment of NAFLD and its downstream events.
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48
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Katsiki N, Mikhailidis DP, Banach M. Lipid-lowering agents for concurrent cardiovascular and chronic kidney disease. Expert Opin Pharmacother 2019; 20:2007-2017. [DOI: 10.1080/14656566.2019.1649394] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Affiliation(s)
- Niki Katsiki
- Diabetes Center, Division of Endocrinology and Metabolism, First Department of Internal Medicine, AHEPA University Hospital, Medical School Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Dimitri P Mikhailidis
- Department of Clinical Biochemistry, Royal Free Hospital Campus, University College London Medical School, University College London (UCL), London, UK
| | - Maciej Banach
- Department of Hypertension, WAM University Hospital in Lodz, Medical University of Lodz, Lodz, Poland
- Polish Mother’s Memorial Hospital Research Institute (PMMHRI), Lodz, Poland
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49
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Püschel GP, Henkel J. Dietary cholesterol does not break your heart but kills your liver. Porto Biomed J 2019; 3:e12. [PMID: 31595236 PMCID: PMC6726297 DOI: 10.1016/j.pbj.0000000000000012] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2018] [Accepted: 05/11/2018] [Indexed: 02/07/2023] Open
Abstract
It is increasingly accepted that dietary cholesterol has a much lower impact on the progression of cardiovascular disease than previously assumed. However, both animal experiments and human studies seem to support the view that dietary cholesterol may contribute to the transition from benign steatosis to the potentially fatal non-alcoholic steatohepatitis. Cholesterol esters and cholesterol accumulate in the hepatocyte and impair its function. This leads to oxidative stress and endoplasmic reticulum stress triggering the release of pro-inflammatory cytokines and rendering the hepatocyte more susceptible to apoptotic or necrotic cell death. Kupffer cells group around dying hepatocytes and phagocytose the hepatocyte debris and lipids. In addition, they are exposed to lipid peroxidation products released from hepatocytes. Kupffer cells, thus activated, release pro-inflammatory, chemotactic and profibrotic cytokines that promote inflammation and fibrosis. Therefore, dietary cholesterol may be harmful to the liver, in particular when administered in combination with polyunsaturated fatty acids that favor lipid peroxidation.
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Affiliation(s)
- Gerhard P Püschel
- Department of Nutritional Biochemistry, University of Potsdam, Institute of Nutritional Science, Nuthetal, Germany
| | - Janin Henkel
- Department of Nutritional Biochemistry, University of Potsdam, Institute of Nutritional Science, Nuthetal, Germany
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50
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Lee Y, Doumouras AG, Yu J, Brar K, Banfield L, Gmora S, Anvari M, Hong D. Complete Resolution of Nonalcoholic Fatty Liver Disease After Bariatric Surgery: A Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol 2019; 17:1040-1060.e11. [PMID: 30326299 DOI: 10.1016/j.cgh.2018.10.017] [Citation(s) in RCA: 244] [Impact Index Per Article: 40.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2018] [Revised: 09/27/2018] [Accepted: 10/01/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Bariatric surgery has been reported to lead to complete resolution of nonalcoholic fatty liver disease (NAFLD) following the sustained weight loss induced in obese patients. We performed a systematic review and meta-analysis to evaluate the effects of bariatric surgery on NAFLD in obese patients. METHODS We searched MEDLINE, EMBASE, CENTRAL, and Web of Science databases through May 2018 for studies that compared liver biopsy results before and after bariatric surgery in obese patients. Primary outcomes were biopsy-confirmed resolution of NAFLD and NAFLD activity score. Secondary outcomes were worsening of NAFLD after surgery and liver volume. The Grading of Recommendations, Assessment, Development, and Evidence approach was conducted to assess overall quality of evidence. RESULTS We analyzed data from 32 cohort studies comprising 3093 biopsy specimens. Bariatric surgery resulted in a biopsy-confirmed resolution of steatosis in 66% of patients (95% CI, 56%-75%), inflammation in 50% (95% CI, 35%-64%), ballooning degeneration in 76% (95% CI, 64%-86%), and fibrosis in 40% (95% CI, 29%-51%). Patients' mean NAFLD activity score was reduced significantly after bariatric surgery (mean difference, 2.39; 95% CI, 1.58-3.20; P < .001). However, bariatric surgery resulted in new or worsening features of NAFLD, such as fibrosis, in 12% of patients (95% CI, 5%-20%). The overall Grading of Recommendations, Assessment, Development, and Evidence quality of evidence was very low. CONCLUSIONS Through this systematic review and meta-analysis, we found that bariatric surgery leads to complete resolution of NAFLD in obese patients. However, some patients develop new or worsened features of NAFLD. Randomized controlled trials are needed to further examine the therapeutic benefits of bariatric surgery for patients with NAFLD.
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Affiliation(s)
- Yung Lee
- Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada; Division of General Surgery, Department of Surgery, McMaster University, Hamilton, Ontario, Canada
| | - Aristithes G Doumouras
- Division of General Surgery, Department of Surgery, McMaster University, Hamilton, Ontario, Canada
| | - James Yu
- Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Karanbir Brar
- Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Laura Banfield
- Health Sciences Library, McMaster University, Hamilton, Ontario, Canada
| | - Scott Gmora
- Division of General Surgery, Department of Surgery, McMaster University, Hamilton, Ontario, Canada
| | - Mehran Anvari
- Division of General Surgery, Department of Surgery, McMaster University, Hamilton, Ontario, Canada
| | - Dennis Hong
- Division of General Surgery, Department of Surgery, McMaster University, Hamilton, Ontario, Canada.
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