Role of patatin-like phospholipase domain-containing 3 on... : Hepatology (original) (raw)

Steatohepatitis/Metabolic Liver Disease

Role of patatin-like phospholipase domain-containing 3 on lipid-induced hepatic steatosis and insulin resistance in rats

Kumashiro, Naoki1,2; Yoshimura, Toru2; Cantley, Jennifer L.1,2; Majumdar, Sachin K.2; Guebre-Egziabher, Fitsum2; Kursawe, Romy3; Vatner, Daniel F.2; Fat, Ioana2; Kahn, Mario2; Erion, Derek M.1,2,4; Zhang, Xian-Man1,2; Zhang, Dongyan1,2,4; Manchem, Vara Prasad5; Bhanot, Sanjay5; Gerhard, Glenn S.6; Petersen, Kitt F.2; Cline, Gary W.2; Samuel, Varman T.2,7; Shulman, Gerald I.1,2,4

1_Howard Hughes Medical Institute, Yale University, School of Medicine, New Haven, CT_

2_Department of Internal Medicine, Yale University School of Medicine, New Haven, CT_

3_Department of Pediatrics, Yale University School of Medicine, New Haven, CT_

4_Department of Cellular & Molecular Physiology, Yale University School of Medicine, New Haven, CT_

5_ISIS Pharmaceuticals, Carlsbad, CA_

6_Weis Center for Research, Geisinger Clinic, Danville, PA_

7_Veterans Affairs Medical Center, West Haven CT_

Address reprint requests to: Gerald I. Shulman, Howard Hughes Medical Institute, Yale University, Department of Internal Medicine, Yale University School of Medicine, P.O. Box 9812, New Haven, CT, 06536-8012

Email:[email protected]

Received 5 September 2012; Accepted 7 November 2012

View this article online atwileyonlinelibrary.com.

Grant sponsor: National Institutes of Health; Grant Numbers: DK-085638 DK-40936 AG-23686 RR-024139 P30 DK-34989 P30 DK-45735; Grant sponsor: VA Merit Grant; Grant sponsor: Manpei Suzuki Diabetes Foundation fellowship; Grant sponsor: Distinguished Clinical Scientist Award from the American Diabetes Association.

Potential conflict of interest: Nothing to report.

fax: 203-737-4059

Abstract

Genome-wide array studies have associated the patatin-like phospholipase domain-containing 3 (PNPLA3) gene polymorphisms with hepatic steatosis. However, it is unclear whether PNPLA3 functions as a lipase or a lipogenic enzyme and whether PNPLA3 is involved in the pathogenesis of hepatic insulin resistance. To address these questions we treated high-fat-fed rats with specific antisense oligonucleotides to decrease hepatic and adipose pnpla3 expression. Reducing pnpla3 expression prevented hepatic steatosis, which could be attributed to decreased fatty acid esterification measured by the incorporation of [U-13C]-palmitate into hepatic triglyceride. While 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, ˜35% reduction in the PA/LPA ratio, and ˜60%-70% reduction in transacylation activity at the level of acyl-CoA:1-acylglycerol-sn-3-phosphate acyltransferase. These changes were associated with an ˜50% reduction in hepatic diacylglycerol (DAG) content, an ˜80% reduction in hepatic protein kinase Cε activation, and increased hepatic insulin sensitivity, as reflected by a 2-fold greater suppression of endogenous glucose production during the hyperinsulinemic-euglycemic clamp. Finally, in humans, hepatic PNPLA3 messenger RNA (mRNA) expression was strongly correlated with hepatic triglyceride and DAG content, supporting a potential lipogenic role of PNPLA3 in humans.

Conclusion:

PNPLA3 may function primarily in a lipogenic capacity and inhibition of PNPLA3 may be a novel therapeutic approach for treatment of nonalcoholic fatty liver disease-associated hepatic insulin resistance.