Björn Carlsson1, Daniel Lindén1,2, Gabriella Brolén3, Mathias Liljeblad1, Mikael Bjursell1, Stefano Romeo4,5,6, Rohit Loomba7. 1. Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden. 2. Division of Endocrinology, Department of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. 3. Precision Medicine, Cardiovascular, Renal and Metabolism, R&D, AstraZeneca, Gothenburg, Sweden. 4. Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden. 5. Clinical Nutrition Unit, Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy. 6. Cardiology Department, Sahlgrenska University Hospital, Gothenburg, Sweden. 7. NAFLD Research Center, Division of Gastroenterology, University of California San Diego, San Diego, CA, USA.
Abstract
BACKGROUND: Non-alcoholic steatohepatitis (NASH) is a severe form of non-alcoholic fatty liver disease (NAFLD) characterised by liver fat accumulation, inflammation and progressive fibrosis. Emerging data indicate that genetic susceptibility increases risks of NAFLD, NASH and NASH-related cirrhosis. AIMS: To review NASH genetics and discuss the potential for precision medicine approaches to treatment. METHOD: PubMed search and inclusion of relevant literature. RESULTS: Single-nucleotide polymorphisms in PNPLA3, TM6SF2, GCKR, MBOAT7 and HSD17B13 are clearly associated with NASH development or progression. These genetic variants are common and have moderate-to-large effect sizes for development of NAFLD, NASH and hepatocellular carcinoma (HCC). The genes play roles in lipid remodelling in lipid droplets, hepatic very low-density lipoprotein (VLDL) secretion and de novo lipogenesis. The PNPLA3 I148M variant (rs738409) has large effects, with approximately twofold increased odds of NAFLD and threefold increased odds of NASH and HCC per allele. Obesity interacts with PNPLA3 I148M to elevate liver fat content and increase rates of NASH. Although the isoleucine-to-methionine substitution at amino acid position 148 of the PNPLA3 enzyme inactivates its lipid remodelling activity, the effect of PNPLA3 I148M results from trans-repression of another lipase (ATGL/PNPLA2) by sequestration of a shared cofactor (CGI-58/ABHD5), leading to decreased hepatic lipolysis and VLDL secretion. In homozygous Pnpla3 I148M knock-in rodent models of NAFLD, targeted PNPLA3 mRNA knockdown reduces hepatic steatosis, inflammation and fibrosis. CONCLUSION: The emerging genetic and molecular understanding of NASH paves the way for novel interventions, including precision medicines that can modulate the activity of specific genes associated with NASH.
BACKGROUND:Non-alcoholic steatohepatitis (NASH) is a severe form of non-alcoholic fatty liver disease (NAFLD) characterised by liver fat accumulation, inflammation and progressive fibrosis. Emerging data indicate that genetic susceptibility increases risks of NAFLD, NASH and NASH-related cirrhosis. AIMS: To review NASH genetics and discuss the potential for precision medicine approaches to treatment. METHOD: PubMed search and inclusion of relevant literature. RESULTS: Single-nucleotide polymorphisms in PNPLA3, TM6SF2, GCKR, MBOAT7 and HSD17B13 are clearly associated with NASH development or progression. These genetic variants are common and have moderate-to-large effect sizes for development of NAFLD, NASH and hepatocellular carcinoma (HCC). The genes play roles in lipid remodelling in lipid droplets, hepatic very low-density lipoprotein (VLDL) secretion and de novo lipogenesis. The PNPLA3 I148M variant (rs738409) has large effects, with approximately twofold increased odds of NAFLD and threefold increased odds of NASH and HCC per allele. Obesity interacts with PNPLA3 I148M to elevate liver fat content and increase rates of NASH. Although the isoleucine-to-methionine substitution at amino acid position 148 of the PNPLA3 enzyme inactivates its lipid remodelling activity, the effect of PNPLA3 I148M results from trans-repression of another lipase (ATGL/PNPLA2) by sequestration of a shared cofactor (CGI-58/ABHD5), leading to decreased hepatic lipolysis and VLDL secretion. In homozygous Pnpla3 I148M knock-in rodent models of NAFLD, targeted PNPLA3 mRNA knockdown reduces hepatic steatosis, inflammation and fibrosis. CONCLUSION: The emerging genetic and molecular understanding of NASH paves the way for novel interventions, including precision medicines that can modulate the activity of specific genes associated with NASH.
Authors: Simona Riccio; Rosa Melone; Caterina Vitulano; Pierfrancesco Guida; Ivan Maddaluno; Stefano Guarino; Pierluigi Marzuillo; Emanuele Miraglia Del Giudice; Anna Di Sessa Journal: World J Clin Pediatr Date: 2022-03-23
Authors: Pierre Deltenre; Jochen Hampe; Felix Stickel; Stephan Buch; Hamish Innes; Hans Dieter Nischalke; Indra Neil Guha; Karl Heinz Weiss; Will Irving; Daniel Gotthardt; Eleanor Barnes; Janett Fischer; M Azim Ansari; Jonas Rosendahl; Shang-Kuan Lin; Astrid Marot; Vincent Pedergnana; Markus Casper; Jennifer Benselin; Frank Lammert; John McLauchlan; Philip L Lutz; Victoria Hamill; Sebastian Mueller; Joanne R Morling; Georg Semmler; Florian Eyer; Johann von Felden; Alexander Link; Arndt Vogel; Jens U Marquardt; Stefan Sulk; Jonel Trebicka; Luca Valenti; Christian Datz; Thomas Reiberger; Clemens Schafmayer; Thomas Berg Journal: Hepatol Commun Date: 2021-12-27