title: Role of patatin-like phospholipase domain-containing 3 on lipid-induced hepatic steatosis and insulin resistance in rats.
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-(13) C]-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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Howard Hughes Medical Institute, Yale University, School of Medicine, New Haven, CT, USA.
authors.forename: Naoki
authors.initials: N
authors.lastname: Kumashiro
authors.forename: Toru
authors.initials: T
authors.lastname: Yoshimura
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Cantley
authors.forename: Sachin K
authors.initials: SK
authors.lastname: Majumdar
authors.forename: Fitsum
authors.initials: F
authors.lastname: Guebre-Egziabher
authors.forename: Romy
authors.initials: R
authors.lastname: Kursawe
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Vatner
authors.forename: Ioana
authors.initials: I
authors.lastname: Fat
authors.forename: Mario
authors.initials: M
authors.lastname: Kahn
authors.forename: Derek M
authors.initials: DM
authors.lastname: Erion
authors.forename: Xian-Man
authors.initials: XM
authors.lastname: Zhang
authors.forename: Dongyan
authors.initials: D
authors.lastname: Zhang
authors.forename: Vara Prasad
authors.initials: VP
authors.lastname: Manchem
authors.forename: Sanjay
authors.initials: S
authors.lastname: Bhanot
authors.forename: Glenn S
authors.initials: GS
authors.lastname: Gerhard
authors.forename: Kitt F
authors.initials: KF
authors.lastname: Petersen
authors.forename: Gary W
authors.initials: GW
authors.lastname: Cline
authors.forename: Varman T
authors.initials: VT
authors.lastname: Samuel
authors.forename: Gerald I
authors.initials: GI
authors.lastname: Shulman
mesh_terms: D000818:Animals; D001706:Biopsy; D059305:Diet, High-Fat / Q000009:adverse effects*; D004075:Diglycerides / Q000378:metabolism; D004195:Disease Models, Animal; D005227:Fatty Acids / Q000378:metabolism; D005234:Fatty Liver / Q000139:chemically induced* / Q000503:physiopathology*; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology*; D008055:Lipids / Q000009:adverse effects*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D054467:Phospholipases A2 / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014280:Triglycerides / Q000378:metabolism; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent
chemical_list: D004075:Diglycerides; D005227:Fatty Acids; D008055:Lipids; D008565:Membrane Proteins; D016376:Oligonucleotides, Antisense; D054467:Phospholipases A2; D012333:RNA, Messenger; D014280:Triglycerides; C572899:PNPLA3 protein, rat; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent