Deficiency of liver adipose triglyceride lipase in mice... : Hepatology (original) (raw)

Steatohepatitis/Metabolic Liver Disease

Deficiency of liver adipose triglyceride lipase in mice causes progressive hepatic steatosis

Wu, Jiang Wei1,2; Wang, Shu Pei2; Alvarez, Fernando3; Casavant, Stéphanie2; Gauthier, Nicolas2; Abed, Lynda4; Soni, Krishnakant G.5; Yang, Gongshe1; Mitchell, Grant A.2

1_Laboratory of Animal Fat Deposition and Muscle Development, College of Animal Science and Technology, Northwest A & F University, Yangling, Shaanxi, China_

2_the Divisions of Medical Genetics_

3_Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics_

4_Department of Pathology, Université de Montréal and CHU Sainte-Justine, Montreal, Quebec, Canada_

5_Cell Biology and Metabolism Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD_

Laboratory of Animal Fat Deposition and Muscle Development, College of Animal Science and Technology, Northwest A & F University, Yangling, Shaanxi, China

Division of Medical Genetics, Department of Pediatrics, Université de Montréal and CHU Sainte-Justine, 3175 Cote Ste-Catherine, Montreal, QC, Canada, H3T 1C5 E-mail:[email protected] or [email protected]

Potential conflict of interest: Nothing to report.

Supported by Canadian Institutes of Health Research Operating Grant 221920 (to G. A. M.).

fax: 514–345–4766

Abstract

Accumulation of cytoplasmic triacylglycerol (TG) underlies hepatic steatosis, a major cause of cirrhosis. The pathways of cytoplasmic TG metabolism are not well known in hepatocytes, but evidence suggests an important role in lipolysis for adipose triglyceride lipase (ATGL). We created mice with liver-specific inactivation of Pnpla2, the ATGL gene. These ATGLLKO mice had severe progressive periportal macrovesicular and pericentral microvesicular hepatic steatosis (73, 150, and 226 μmol TG/g liver at 4, 8, and 12 months, respectively). However, plasma levels of glucose, TG, and cholesterol were similar to those of controls. Fasting 3-hydroxybutyrate level was normal, but in thin sections of liver, beta oxidation of palmitate was decreased by one-third in ATGLLKO mice compared with controls. Tests of very low-density lipoprotein production, glucose, and insulin tolerance and gluconeogenesis from pyruvate were normal. Plasma alanine aminotransferase levels were elevated in ATGLLKO mice, but histological estimates of inflammation and fibrosis and messenger RNA (mRNA) levels of tumor necrosis factor-α and interleukin-6 were similar to or lower than those in controls. ATGLLKO cholangiocytes also showed cytoplasmic lipid droplets, demonstrating that ATGL is also a major lipase in cholangiocytes. There was a 50-fold reduction of hepatic diacylglycerol acyltransferase 2 mRNA level and a 2.7-fold increase of lipolysosomes in hepatocytes (P < 0.001), suggesting reduced TG synthesis and increased lysosomal degradation of TG as potential compensatory mechanisms. Conclusion: Compared with the hepatic steatosis of obesity and diabetes, steatosis in ATGL deficiency is well tolerated metabolically. ATGLLKO mice will be useful for studying the pathophysiology of hepatic steatosis. (HEPATOLOGY 2011;)