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

• Published in: European journal of pharmacology Vol. 691; no. 1-3; pp. 9 - 18
• Main Authors: Dal Rhee, Sang, Kim, Chi-Hyun, Seon Park, Ji, Hoon Jung, Won, Bum Park, Sung, Youn Kim, Hee, Hwan Bae, Gyu, Jan Kim, Ta, Young Kim, Ki
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 15.09.2012
• Subjects: animal models; Animals; Apoptosis; Apoptosis - drug effects; Carbenoxolone - pharmacology; cytochrome c; cytokines; Cytokines - genetics; Enzyme Inhibitors - pharmacology; Fatty Acids, Nonesterified - metabolism; Fatty liver; Fatty Liver - metabolism; Fatty Liver - pathology; Fatty Liver - prevention & control; fatty-acid synthase; free fatty acids; Gene Expression Regulation - drug effects; glucose tolerance; Glycyrrhiza glabra; Hep G2 Cells; human cell lines; Humans; Inflammation; insulin resistance; licorice; lipogenesis; Lipogenesis - drug effects; liver; Liver - drug effects; Liver - injuries; Liver - metabolism; Liver - pathology; Male; Mice; Mice, Inbred C57BL; Mitochondria - drug effects; Mitochondria - metabolism; mitochondrial membrane; Non-alcoholic Fatty Liver Disease; obesity; oleic acid; patients; pharmacology; protective effect; Reactive oxygen species; Reactive Oxygen Species - metabolism; Sterol Regulatory Element Binding Protein 1 - antagonists & inhibitors; Sterol Regulatory Element Binding Protein 1 - genetics; Sterol Regulatory Element Binding Protein 1 - metabolism; Sterol regulatory element binding protein-1c; triacylglycerols; Triglycerides - metabolism; Reactive oxygen species; Inflammation; Fatty liver; Sterol regulatory element binding protein-1c; Apoptosis
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2012.06.021

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-Lepob/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-Lepob/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-Lepob/ob mice. Carbenoxolone also prevented hepatic injury through anti-apoptotic action in the livers of C57BL/6-Lepob/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-Lepob/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-Lepob/ob mice. It is suggested that carbenoxolone prevents the development and progression of fatty liver disease in patients with insulin resistance. Model for the mechanisms by which carbenoxolone inhibit development of the fatty liver in C57BL/6J-Lepob/ob mice. [Display omitted]