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2019, Hepatology
Nature Reviews Gastroenterology & Hepatology
Lipid droplets and liver disease: from basic biology to clinical implications2017 •
Biomedicines
Genetics Is of the Essence to Face NAFLDNonalcoholic fatty liver disease (NAFLD) is the commonest cause of chronic liver disease worldwide. It is closely related to obesity, insulin resistance (IR) and dyslipidemia so much so it is considered the hepatic manifestation of the Metabolic Syndrome. The NAFLD spectrum extends from simple steatosis to nonalcoholic steatohepatitis (NASH), a clinical condition which may progress up to fibrosis, cirrhosis and hepatocellular carcinoma (HCC). NAFLD is a complex disease whose pathogenesis is shaped by both environmental and genetic factors. In the last two decades, several heritable modifications in genes influencing hepatic lipid remodeling, and mitochondrial oxidative status have been emerged as predictors of progressive hepatic damage. Among them, the patatin-like phospholipase domain-containing 3 (PNPLA3) p.I148M, the Transmembrane 6 superfamily member 2 (TM6SF2) p.E167K and the rs641738 membrane bound-o-acyltransferase domain-containing 7 (MBOAT7) polymorphisms are considered th...
2020 •
Journal of Clinical Investigation
Chronic overexpression of PNPLA3I148M in mouse liver causes hepatic steatosis2012 •
Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids
Recombinant PNPLA3 protein shows triglyceride hydrolase activity and its I148M mutation results in loss of function2014 •
Exploration of Medicine
Genetic and metabolic factors: the perfect combination to treat metabolic associated fatty liver diseaseThe prevalence of nonalcoholic or more recently re-defined metabolic associated fatty liver disease (MAFLD) is rapidly growing worldwide. It is characterized by hepatic fat accumulation exceeding 5% of liver weight not attributable to alcohol consumption. MAFLD refers to an umbrella of conditions ranging from simple steatosis to nonalcoholic steatohepatitis which may finally progress to cirrhosis and hepatocellular carcinoma. MAFLD is closely related to components of the metabolic syndrome and to environmental factors. In addition to the latter, genetic predisposition plays a key role in MAFLD pathogenesis and strictly contributes to its progressive forms. The candidate genes which have been related to MAFLD hereditability are mainly involved in lipids remodeling, lipid droplets assembly, lipoprotein packaging and secretion, de novo lipogenesis, and mitochondrial redox status. In the recent years, it has emerged the opportunity to translate the genetics into clinics by aggregating t...
International Journal of Molecular Sciences
The Propensity of the Human Liver to Form Large Lipid Droplets Is Associated with PNPLA3 Polymorphism, Reduced INSIG1 and NPC1L1 Expression and Increased Fibrogenetic Capacity2021 •
In nonalcoholic steatohepatitis animal models, an increased lipid droplet size in hepatocytes is associated with fibrogenesis. Hepatocytes with large droplet (Ld-MaS) or small droplet (Sd-MaS) macrovesicular steatosis may coexist in the human liver, but the factors associated with the predominance of one type over the other, including hepatic fibrogenic capacity, are unknown. In pre-ischemic liver biopsies from 225 consecutive liver transplant donors, we retrospectively counted hepatocytes with Ld-MaS and Sd-MaS and defined the predominant type of steatosis as involving ≥50% of steatotic hepatocytes. We analyzed a donor Patatin-like phospholipase domain-containing protein 3 (PNPLA3) rs738409 polymorphism, hepatic expression of proteins involved in lipid metabolism by RT-PCR, hepatic stellate cell (HSC) activation by α-SMA immunohistochemistry and, one year after transplantation, histological progression of fibrosis due to Hepatitis C Virus (HCV) recurrence. Seventy-four livers had n...
Journal of Lipid Research
Pnpla3/Adiponutrin deficiency in mice does not contribute to fatty liver disease or metabolic syndrome2010 •
Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are emerging worldwide epidemics, projected to become the leading cause of liver transplants. The strongest genetic risk factor for NAFLD/NASH susceptibility and progression is a single-nucleotide polymorphism (SNP) in the patatin-like phospholipase domain-containing 3 gene (PNPLA3), rs738409, encoding the missense mutation I148M. This aminoacidic substitution interferes with the normal remodeling of lipid droplets in hepatocytes. It is also thought to play a key role in promoting liver fibrosis by inhibiting the release of retinol from hepatic stellate cells. Reducing PNPLA3 levels in individuals homozygous for 148M may be an effective treatment for the entire spectrum of NAFLD, based on gene dosage analysis in the human population, as well as the protective effect of another naturally occurring SNP (rs2294918) in PNPLA3 which, when co-inherited, reduces PNPLA3 mRNA levels to 50% and counteracts dise...
Annual Review of Biochemistry
Lipid Droplets and Cellular Lipid Metabolism2012 •
Nucleic Acid Therapeutics
Identification and Optimization of a Minor Allele-Specific siRNA to Prevent PNPLA3 I148M-Driven Nonalcoholic Fatty Liver Disease2021 •
2013 •
2017 •
Hepatology (Baltimore, Md.)
The rs2294918 E434K variant modulates PNPLA3 expression and liver damage2015 •
Journal of Hepatology
Fasting-induced G0/G1 switch gene 2 and FGF21 expression in the liver are under regulation of adipose tissue derived fatty acids2015 •
Digestive and Liver Disease
PNPLA3 I148M variant and hepatocellular carcinoma: A common genetic variant for a rare disease2013 •
Acta Dermato Venereologica
Molecular Genetics of Keratinization Disorders – What’s New About IchthyosisInternational Journal of Molecular Sciences
Nutrition and Genetics in NAFLD: The Perfect BinomiumInternational Journal of Molecular Sciences
Genetic and Diet-Induced Animal Models for Non-Alcoholic Fatty Liver Disease (NAFLD) ResearchJournal of Biological Chemistry
The Hepatitis C Virus Core Protein Inhibits Adipose Triglyceride Lipase (ATGL)-mediated Lipid Mobilization and Enhances the ATGL Interaction with Comparative Gene Identification 58 (CGI-58) and Lipid Droplets2014 •
2020 •
American journal of physiology. Endocrinology and metabolism
From whole body to cellular models of hepatic triglyceride metabolism: man has got to know his limitations2015 •
Journal of Clinical Medicine
The Role of Insulin Resistance in Fueling NAFLD Pathogenesis: From Molecular Mechanisms to Clinical ImplicationsJournal of Personalized Medicine
Is HSD17B13 Genetic Variant a Protector for Liver Dysfunction? Future Perspective as a Potential Therapeutic Target2021 •
2021 •
2019 •
Middle East Journal of Digestive Diseases
Assessment of Genetic Aspects of Non-alcoholic Fatty Liver and Premature Cardiovascular Events2020 •
International Journal of Molecular Sciences
Genetic and Epigenetic Modifiers of Alcoholic Liver DiseaseFood Research International
The PNPLA3 I148M variant and chronic liver disease: When a genetic mutation meets nutrients2014 •
Wellcome Open Research
Methyl donor deficient diets cause distinct alterations in lipid metabolism but are poorly representative of human NAFLD2017 •
Journal of Hepatology
Distinct regulation of adiponutrin/PNPLA3 gene expression by the transcription factors ChREBP and SREBP1c in mouse and human hepatocytes2011 •
2022 •
World Journal of Gastroenterology
PNPLA3 I148M polymorphism and progressive liver disease2013 •
Human Molecular Genetics
PNPLA3 overexpression results in reduction of proteins predisposing to fibrosis2016 •
Clinics and research in hepatology and gastroenterology
Association study of PNPLA2 gene with histological parameters of NAFLD in an obese population2015 •
The American Journal of Clinical Nutrition
Isoleucine-to-methionine substitution at residue 148 variant of PNPLA3 gene and metabolic outcomes in gestational diabetes2014 •
Journal of Biological Chemistry
Hepatitis C Virus Core Protein Decreases Lipid Droplet Turnover: A MECHANISM FOR CORE-INDUCED STEATOSIS2011 •
International Journal of Molecular Sciences
Hepatic Lipid Catabolism via PPARα-Lysosomal Crosstalk2020 •