Hepatic overexpression of hormone-sensitive lipase and adipose triglyceride lipase promotes fatty acid oxidation, stimulates direct release of free fatty acids, and ameliorates steatosis

Brendan N. Reid, Gene P. Ables, Oleg A. Otlivanchik, Gabriele Schoiswohl, Rudolf Zechner, William S. Blaner, Ira J. Goldberg, Robert F. Schwabe, Streamson C. Chua, Jr., Li Shin Huang

Research output: Contribution to journalArticle

172 Citations (Scopus)

Abstract

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-β-hydroxybutyrate levels were increased 3-5 days after infection in both HSL- and ATGL-overexpressing male mice, suggesting an increase in β-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 β-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.

Original languageEnglish (US)
Pages (from-to)13087-13099
Number of pages13
JournalJournal of Biological Chemistry
Volume283
Issue number19
DOIs
StatePublished - May 9 2008

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Sterol Esterase
Lipase
Nonesterified Fatty Acids
Fatty Acids
Triglycerides
Oxidation
Liver
Obesity
Lipolysis
Enzymes
Insulin
Lipids
Plasmas
Insulin Resistance
3-Hydroxybutyric Acid
Apolipoproteins B
Oleic Acid
Nutrition
High Fat Diet
Fatty Liver

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

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Hepatic overexpression of hormone-sensitive lipase and adipose triglyceride lipase promotes fatty acid oxidation, stimulates direct release of free fatty acids, and ameliorates steatosis. / Reid, Brendan N.; Ables, Gene P.; Otlivanchik, Oleg A.; Schoiswohl, Gabriele; Zechner, Rudolf; Blaner, William S.; Goldberg, Ira J.; Schwabe, Robert F.; Chua, Jr., Streamson C.; Huang, Li Shin.

In: Journal of Biological Chemistry, Vol. 283, No. 19, 09.05.2008, p. 13087-13099.

Research output: Contribution to journalArticle

Reid, Brendan N. ; Ables, Gene P. ; Otlivanchik, Oleg A. ; Schoiswohl, Gabriele ; Zechner, Rudolf ; Blaner, William S. ; Goldberg, Ira J. ; Schwabe, Robert F. ; Chua, Jr., Streamson C. ; Huang, Li Shin. / Hepatic overexpression of hormone-sensitive lipase and adipose triglyceride lipase promotes fatty acid oxidation, stimulates direct release of free fatty acids, and ameliorates steatosis. In: Journal of Biological Chemistry. 2008 ; Vol. 283, No. 19. pp. 13087-13099.
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T1 - Hepatic overexpression of hormone-sensitive lipase and adipose triglyceride lipase promotes fatty acid oxidation, stimulates direct release of free fatty acids, and ameliorates steatosis

AU - Reid, Brendan N.

AU - Ables, Gene P.

AU - Otlivanchik, Oleg A.

AU - Schoiswohl, Gabriele

AU - Zechner, Rudolf

AU - Blaner, William S.

AU - Goldberg, Ira J.

AU - Schwabe, Robert F.

AU - Chua, Jr., Streamson C.

AU - Huang, Li Shin

PY - 2008/5/9

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N2 - 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-β-hydroxybutyrate levels were increased 3-5 days after infection in both HSL- and ATGL-overexpressing male mice, suggesting an increase in β-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 β-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.

AB - 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-β-hydroxybutyrate levels were increased 3-5 days after infection in both HSL- and ATGL-overexpressing male mice, suggesting an increase in β-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 β-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.

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