Carbenoxolone prevents the development of fatty liver in C57BL/6-Lep ob/ob mice via the inhibition of sterol regulatory element binding protein-1c activity and apoptosis.

Abstract

Carbenoxolone is the 3-hemisuccinate of glycyrrhetinic acid, the active principal of licorice (Glycyrrhiza glabra). It was reported that carbenoxolone improved glucose tolerance with increased insulin sensitivity in mice with high fat diet-induced obesity. In the present study, we elucidated the protective effect of carbenoxolone in fatty liver animal models of C57BL/6-Lep(ob/ob) mice through inhibition of hepatic lipogenesis and apoptosis. In addition, the potential mechanisms by which carbenoxolone could exert such protection were elucidated. Carbenoxolone was daily administrated by gavage for 28 days in C57BL/6 and C57BL/6-Lep(ob/ob) mice. Carbenoxolone prevented the plasma triglyceride and free fatty acid accumulation associated with the reduction of the expression of sterol regulatory element binding protein-1c, liver X receptor, fatty acid synthase and acethyl-CoA carboxylase in the livers of C57BL/6-Lep(ob/ob) mice. Carbenoxolone also prevented hepatic injury through anti-apoptotic action in the livers of C57BL/6-Lep(ob/ob) mice, accompanied by increased Bcl-2 expression and suppressed Bax and cytochrome c expression. As a mechanism, increased inflammatory cytokine expressions were inhibited by carbenoxolone in the fatty livers of C57BL/6-Lep(ob/ob) mice. Furthermore, carbenoxolone inhibited free fatty acid (oleate/palmitate) induced reactive oxygen species formation and reversed free fatty acid induced mitochondrial membrane depolarization in HepG2 cells. Carbenoxolone prevents the development of fatty liver by inhibiting sterol regulatory element binding protein-1c expression and activity with an anti-apoptotic mechanism via the inhibition of inflammatory cytokine and reactive oxygen species formation in the livers of C57BL/6-Lep(ob/ob) mice. It is suggested that carbenoxolone prevents the development and progression of fatty liver disease in patients with insulin resistance.

• Authors: Sang Dal Rhee, Chi-Hyun Kim, Ji Seon Park, Won Hoon Jung, Sung Bum Park, Hee Youn Kim, Gyu Hwan Bae, Ta Jan Kim, Ki Young Kim
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 691 Issue 1-3 Pg. 9-18 (Sep 15 2012) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 22742899 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier B.V. All rights reserved.

Chemical References

• Cytokines
• Enzyme Inhibitors
• Fatty Acids, Nonesterified
• Reactive Oxygen Species
• Sterol Regulatory Element Binding Protein 1
• Triglycerides
• Carbenoxolone

Topics

• Animals
• Apoptosis (drug effects)
• Carbenoxolone (pharmacology)
• Cytokines (genetics)
• Enzyme Inhibitors (pharmacology)
• Fatty Acids, Nonesterified (metabolism)
• Fatty Liver (metabolism, pathology, prevention & control)
• Gene Expression Regulation (drug effects)
• Hep G2 Cells
• Humans
• Lipogenesis (drug effects)
• Liver (drug effects, injuries, metabolism, pathology)
• Male
• Mice
• Mice, Inbred C57BL
• Mitochondria (drug effects, metabolism)
• Non-alcoholic Fatty Liver Disease
• Reactive Oxygen Species (metabolism)
• Sterol Regulatory Element Binding Protein 1 (antagonists & inhibitors, genetics, metabolism)
• Triglycerides (metabolism)