Hepatic overexpression of hormone-sensitive lipase and adipose triglyceride lipase promotes fatty acid oxidation, stimulates direct release of free fatty acids, and ameliorates steatosis.
Hepatic steatosis is often associated with insulin resistance and obesity and can lead to steatohepatitis and cirrhosis. In this study, we have demonstrated that hormone-sensitive lipase (HSL) and adipose triglyceride lipase (ATGL), two enzymes critical for lipolysis in adipose tissues, also contribute to lipolysis in the liver and can mobilize hepatic triglycerides in vivo and in vitro. Adenoviral overexpression of HSL and/or ATGL reduced liver triglycerides by 40-60% in both ob/ob mice and mice with high fat diet-induced obesity. However, these enzymes did not affect fasting plasma triglyceride and free fatty acid levels or triglyceride and apolipoprotein B secretion rates. Plasma 3-beta-hydroxybutyrate levels were increased 3-5 days after infection in both HSL- and ATGL-overexpressing male mice, suggesting an increase in beta-oxidation. Expression of genes involved in fatty acid transport and synthesis, lipid storage, and mitochondrial bioenergetics was unchanged. Mechanistic studies in oleate-supplemented McA-RH7777 cells with adenoviral overexpression of HSL or ATGL showed that reduced cellular triglycerides could be attributed to increases in beta-oxidation as well as direct release of free fatty acids into the medium. In summary, hepatic overexpression of HSL or ATGL can promote fatty acid oxidation, stimulate direct release of free fatty acid, and ameliorate hepatic steatosis. This study suggests a direct functional role for both HSL and ATGL in hepatic lipid homeostasis and identifies these enzymes as potential therapeutic targets for ameliorating hepatic steatosis associated with insulin resistance and obesity.
Reid
Brendan N
BN
Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, New York 10032, USA.
Ables
Gene P
GP
Otlivanchik
Oleg A
OA
Schoiswohl
Gabriele
G
Zechner
Rudolf
R
Blaner
William S
WS
Goldberg
Ira J
IJ
Schwabe
Robert F
RF
Chua
Streamson C
SC
Huang
Li-Shin
LS
D020155:3-Hydroxybutyric Acid / Q000378:metabolism; D000273:Adipose Tissue / Q000201:enzymology*; D000818:Animals; D001055:Apolipoproteins B / Q000378:metabolism; D002265:Carboxylic Ester Hydrolases / Q000378:metabolism*; D002460:Cell Line; D005215:Fasting; D005230:Fatty Acids, Nonesterified / Q000378:metabolism*; D005234:Fatty Liver / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D008049:Lipase; D050155:Lipogenesis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010084:Oxidation-Reduction; D010641:Phenotype; D002787:Sterol Esterase / Q000235:genetics / Q000378:metabolism*; D014280:Triglycerides / Q000378:metabolism; D015854:Up-Regulation; D000217:Acyltransferases
D020155:3-Hydroxybutyric Acid; D001055:Apolipoproteins B; D002265:Carboxylic Ester Hydrolases; D005230:Fatty Acids, Nonesterified; D008049:Lipase; D002787:Sterol Esterase; D014280:Triglycerides; C494445:PNPLA2 protein, mouse; D000217:Acyltransferases