PNPLA3 expression and its impact on the liver: current perspectives

Bruschi, Francesca Virginia; Tardelli, Matteo; Claudel, Thierry; Trauner, Michael

doi:10.2147/hmer.s125718

Cited by 64 publications

(69 citation statements)

References 90 publications

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“…A volcano plot demonstrates that the genes significantly down‐regulated by Elovl6 deficiency (Supporting Fig. D) included patatin‐like phospholipase domain containing 3 ( Pnpla3 ), which encodes a membrane‐bound protein with a predominant TAG lipase activity . Quantitative real‐time PCR analysis confirmed that Pnpla3 expression was increased 67‐fold by HSD feeding in the liver of Flox mice and reduced by 68% in the liver of LKO mice (Fig.…”

Section: Resultsmentioning

confidence: 81%

Hepatocyte ELOVL Fatty Acid Elongase 6 Determines Ceramide Acyl‐Chain Length and Hepatic Insulin Sensitivity in Mice

et al. 2020

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BaCKgRoUND aND aIMS:Dysfunctional hepatic lipid metabolism is a cause of nonalcoholic fatty liver disease (NAFLD), the most common chronic liver disorder worldwide, and is closely associated with insulin resistance and type 2 diabetes. ELOVL fatty acid elongase 6 (Elovl6) is responsible for converting C16 saturated and monounsaturated fatty acids (FAs) into C18 species. We have previously shown that Elovl6 contributes to obesity-induced insulin resistance by modifying hepatic C16/C18-related FA composition. appRoaCH aND ReSUltS: To define the precise molecular mechanism by which hepatic Elovl6 affects energy homeostasis and metabolic disease, we generated liverspecific Elovl6 knockout (LKO) mice. Unexpectedly, LKO mice were not protected from high-fat diet-induced insulin resistance. Instead, LKO mice exhibited higher insulin sensitivity than controls when consuming a high-sucrose diet (HSD), which induces lipogenesis. Hepatic patatinlike phospholipase domain-containing protein 3 (Pnpla3) expression was down-regulated in LKO mice, and adenoviral Pnpla3 restoration reversed the enhancement in insulin sensitivity in HSD-fed LKO mice. Lipidomic analyses showed that the hepatic ceramide(d18:1/18:0) content was lower in

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Section: Resultsmentioning

confidence: 81%

Hepatocyte ELOVL Fatty Acid Elongase 6 Determines Ceramide Acyl‐Chain Length and Hepatic Insulin Sensitivity in Mice

et al. 2020

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“…PNPLA3 is a member of a family of patatin‐domain containing lipid hydrolases with specificity for an array of different substrates, including triacylglycerols, phospholipids and retinol esters 106 . PNPLA3 expression levels are highest in hepatocytes and hepatic stellate cells in humans and in adipocytes in mice, followed by the retina and other tissues in both species 22 . High carbohydrate levels upregulate PNPLA3 levels in mice 107,108 and in human hepatocytes 109,110 by increasing transcription and reducing protein turnover.…”

Section: Pnpla3 Precision Medicine In Patients With Nashmentioning

confidence: 99%

Review article: the emerging role of genetics in precision medicine for patients with non‐alcoholic steatohepatitis

Carlsson

Lindén

Brolén

et al. 2020

Aliment Pharmacol Ther

118

107

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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. and Sanofi. Rohit Loomba is co-founder of Liponexus, Inc and has served as a speaker, a consultant or an advisory board member for

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“…Insulin and retinol regulate PNPLA3 expression. The PNPLA3 I148M mutation leads to the loss of enzymatic activity and subsequent changes in triglyceride metabolism and is associated with ALD, non-alcoholic fatty liver disease (NAFLD), and HCC [42]. The role of this mutation in the alterations in retinol metabolism is less clear.…”

Section: Hepatic Stellate Cellsmentioning

confidence: 99%

Metabolic Hallmarks of Hepatic Stellate Cells in Liver Fibrosis

Khomich

Ivanov

Bartosch

2019

Cells

142

154

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Liver fibrosis is a regenerative process that occurs after injury. It is characterized by the deposition of connective tissue by specialized fibroblasts and concomitant proliferative responses. Chronic damage that stimulates fibrogenic processes in the long-term may result in the deposition of excess matrix tissue and impairment of liver functions. End-stage fibrosis is referred to as cirrhosis and predisposes strongly to the loss of liver functions (decompensation) and hepatocellular carcinoma. Liver fibrosis is a pathology common to a number of different chronic liver diseases, including alcoholic liver disease, non-alcoholic fatty liver disease, and viral hepatitis. The predominant cell type responsible for fibrogenesis is hepatic stellate cells (HSCs). In response to inflammatory stimuli or hepatocyte death, HSCs undergo trans-differentiation to myofibroblast-like cells. Recent evidence shows that metabolic alterations in HSCs are important for the trans-differentiation process and thus offer new possibilities for therapeutic interventions. The aim of this review is to summarize current knowledge of the metabolic changes that occur during HSC activation with a particular focus on the retinol and lipid metabolism, the central carbon metabolism, and associated redox or stress-related signaling pathways.Most of the progress that has been made in the identification of the molecular mechanisms underlying fibrosis is based on the use of in vitro model systems using tissue culture-adapted HSC lines, primary HSC preparations, and a number of in vivo models such as animals being fed high-fat/cholesterol or choline-deficient diets, animals that undergo bile duct ligation, treatment with ethanol, CCl 4 or other chemical agents, or transgenic animals [5]. Hepatic Stellate CellsThe cell type that is predominantly responsible for fibrotic processes is hepatic stellate cells (HSCs), a mesenchymal cell population that constitutes 5-10% of the total number of cells in the liver (Figure 1). HSCs are located in the perisinusoidal space (space of Disse) and are surrounded by hepatocytes and sinusoidal endothelial cells [6,7]. Their main functions are the secretion of laminin, proteoglycans, and type IV collagen to form basement membrane-like structures. Quiescent HSCs start to proliferate and undergo trans-differentiation into contractile myofibroblasts in response to paracrine stimulation by neighboring cell types, including Kupffer cells, hepatocytes, platelets, leukocytes, and sinusoidal endothelial cells. Kupffer cells can stimulate activation and proliferation of HSCs through the actions of cytokines, and in particular transforming growth factor β1 (TGFβ1), interleukin 1 (IL-1), tumor necrosis factor (TNF), reactive oxygen species (ROS) and lipid peroxides [6,8]. Hepatocytes are an important source of inflammatory lipid peroxides in liver diseases. Platelets release pro-fibrogenic growth factors such as platelet-derived growth factor (PDGF), TGFβ1, and epidermal growth factor (EGF). Neutrophils are an important source of RO...

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PNPLA3 expression and its impact on the liver: current perspectives

Cited by 64 publications

References 90 publications

Hepatocyte ELOVL Fatty Acid Elongase 6 Determines Ceramide Acyl‐Chain Length and Hepatic Insulin Sensitivity in Mice

Hepatocyte ELOVL Fatty Acid Elongase 6 Determines Ceramide Acyl‐Chain Length and Hepatic Insulin Sensitivity in Mice

Review article: the emerging role of genetics in precision medicine for patients with non‐alcoholic steatohepatitis

Metabolic Hallmarks of Hepatic Stellate Cells in Liver Fibrosis

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