Y Bhanot,five Glenn S. Gerhard,six Kitt F. Petersen,2 Gary W. Cline

Y Bhanot,five Glenn S. Gerhard,six Kitt F. Petersen,two Gary W. Cline,2 Varman T. Samuel,two,7 and Gerald I. Shulman1,2,Genome-wide array studies have linked the patatin-like phospholipase domaincontaining 3 (PNPLA3) gene polymorphisms with hepatic steatosis. Having said that, it can be unclear whether PNPLA3 functions as a lipase or perhaps a lipogenic enzyme and regardless of whether PNPLA3 is involved within the pathogenesis of hepatic insulin resistance. To address these concerns we treated high-fat-fed rats with distinct antisense oligonucleotides to reduce hepatic and adipose pnpla3 expression. Reducing pnpla3 expression prevented hepatic steatosis, which could possibly be attributed to decreased fatty acid esterification measured by the incorporation of [U-13C]-palmitate into hepatic triglyceride. Even though the precursors for phosphatidic acid (PA) (long-chain fatty acyl-CoAs and lysophosphatidic acid [LPA]) were not decreased, we did observe an 20 reduction in the hepatic PA content material, 35 reduction in the PA/ LPA ratio, and 60 -70 reduction in transacylation activity in the degree of acyl-CoA:1acylglycerol-sn-3-phosphate acyltransferase. These alterations have been connected with an 50 reduction in hepatic diacylglycerol (DAG) content material, an 80 reduction in hepatic protein kinase Ce activation, and increased hepatic insulin sensitivity, as reflected by a 2-fold higher suppression of endogenous glucose production for the duration of the hyperinsulinemic-euglycemic clamp. Lastly, in humans, hepatic PNPLA3 messenger RNA (mRNA) expression was strongly correlated with hepatic triglyceride and DAG content, supporting a potential lipogenic part of PNPLA3 in humans. Conclusion: PNPLA3 could function primarily inside a lipogenic capacity and inhibition of PNPLA3 may well be a novel therapeutic approach for treatment of nonalcoholic fatty liver disease-associated hepatic insulin resistance.(HEPATOLOGY 2013;57:1763-1772)onalcoholic fatty liver illness (NAFLD) is linked with hepatic insulin resistance, a significant element in the pathogenesis of sort 2 diabetes (T2D) plus the metabolic syndrome.1,two Whilst patients carrying the I148M polymorphism in the patatin-like phospholipase domain-containingN(PNPLA3, also known as adiponutrin or calciumindependent phospholipase A2-epsilon) gene are prone to building hepatic steatosis, the mechanism by which this occurs remains unknown.3-9 PNPLA3 has been reported to possess both triacylglycerol lipase and acylglycerol transacylase activities, specificallyAbbreviations: ACC, acetyl-CoA carboxylase; AGPAT, acyl-CoA:1-acylglycerol-sn-3-phosphate acyltransferase; ALT, alanine aminotransferase; APE, atom percentage of enrichment; ASOs, antisense oligonucleotides; ATGL, adipocyte triglyceride lipase; DAG, diacylglycerol; FAS, fatty acid synthase; HFF, high-fat fed; HOMA-IR, homeostatic model assessment of insulin resistance index; LC-MS/MS, liquid chromatography-mass spectrometry / mass spectrometry; LCCoAs, longchain fatty acyl-CoAs; LPA, lysophosphatidic acid; NAFLD, nonalcoholic fatty liver illness; PKCe, protein kinase Ce; PA, phosphatidic acid; PNPLA3, patatinlike phospholipase domain-containing 3; T2D, type 2 diabetes.Bromothymol Blue From the 1Howard Hughes Healthcare Institute, Yale University, College of Medicine, New Haven, CT; 2Department of Internal Medicine, Yale University School of Medicine, New Haven, CT; 3Department of Pediatrics, Yale University College of Medicine, New Haven, CT; 4Department of Cellular Molecular Physiology, Yale University School of Medicine, New Haven, CT; 5ISIS Pharmac.Dronedarone PMID:23829314