AMP-activated protein kinase (AMPK) and phosphorylated acetyl-CoA carboxylase. Consistent with the activation of AMPK, Rb1 stimulated the expression of genes encoding fatty acid oxidative enzymes and proteins, and suppressed the expression of genes encoding enzymes

This article is available online at http://www.jlr.org strongly associated with obesity and insulin resistance ( 1 ). Fatty liver is characterized by an increased content of hepatocellular lipids and is frequently associated with steatohepatitis and hepatocellular injury, which eventually may result in severe liver damage including bridging fi brosis and cirrhosis ( 2 ). Although the molecular mechanisms underlying fatty liver are not fully understood, dysregulation of hepatic lipid homeostasis caused by pathological conditions such as reduced fatty acid oxidation, enhanced de novo lipogenesis, elevated hepatic fatty acid infl ux, and/ or increased systemic insulin resistance are thought to be important in the development of fatty liver ( 3 ). Indeed, therapies aimed at reducing body weight and/or alleviating insulin resistance reduce fatty liver ( 4 ). AMP-activated protein kinase (AMPK) is an intracellular fuel sensor important in the regulation of lipid metabolism ( 5 ). In the liver, activation of AMPK leads to increased fatty acid oxidation and simultaneously to decreased lipid synthesis ( 6 ). Of interest, antidiabetic drugs, including metformin and the thiazolidinediones, alleviate fatty liver in humans and rodents by regulating lipid metabolism through AMPK activation ( 7 ). Thus AMPK represents an attractive target for therapeutic intervention in the treatment of hepatic disorders ( 8 ). Ginsenoside Rb1 (Rb1), a natural compound extracted from ginseng root, has a glucose-lowering action in vitro ( 9 ), and we have demonstrated that Rb1 signifi cantly reduces body weight, improves glucose tolerance, and enhances insulin action in high-fat diet (HFD)-induced obese rats ( 10 ). These fi ndings prompted us to ask whether Rb1 Abstract Ginsenoside Rb1 (Rb1), a natural compound extracted from ginseng, exerts anti-obesity activity and improves insulin sensitivity in high-fat diet (HFD)-induced obese rats. The objective of the current study was to evaluate the protective effect of Rb1 on fatty liver in HFD-induced obese rats and to elucidate underlying mechanisms. After chronic intraperitoneal administration, Rb1 (10 mg/kg) signifi cantly ameliorated hepatic fat accumulation in HFD-induced obese rats, as demonstrated by reduced liver weight, hepatic triglyceride content, and histological evaluation of liver sections by hematoxylin and eosin and Oil Red O staining. Using primary cultured rat hepatic cells, we found that the rate of fatty acid oxidation and the activity of carnitine palmitoyltransferase 1 (CPT1), a key enzyme in fatty acid -oxidation, were signifi cantly elevated in Rb1-treated hepatocytes compared with those of vehicle-treated cells. HPLC analysis revealed that Rb1 increased the cellular AMP/ATP ratio, which is associated with elevated activation of hepatic AMP-activated protein kinase (AMPK) and phosphorylated acetyl-CoA carboxylase. Consistent with the activation of AMPK, Rb1 stimulated the expression of genes encoding fatty acid oxidative enzymes and proteins, and suppressed the expression of genes encoding enzymes or proteins that function in lipogenesis, assessed by quantitative PCR. We conclude that Rb1 has a potent ability to reduce hepatic fat accumulation and might be useful as a therapeutic agent for fatty liver disorder. —Shen, L., Y. Xiong, D. Q-H. Wang, P. Howles, J. E. Basford, J. Wang, Y. Q. Xiong, D. Y. Hui, S. C. Woods, and M. Liu. Gensenoside Rb1 reduces fatty liver by activating AMP-activated protein kinase in obese rats. J. Lipid Res. 2013. 54: 1430–1438.