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.