The purpose of this project is to determine the mechanisms by which leptin regulates the ABCG5 ABCG8 (G5G8) sterol transporter and influences cholesterol metabolism in obesity. Obesity and diabetes (diabesity) are associated with increased risk of cardiovascular and gallbladder disease, elevated plasma cholesterol levels, and a predilection for cholesterol synthesis rather than absorption. High-fat diets induce a virtually identical phenotype in mice. In contrast, mice that lack leptin (ob/ob) or its receptor (db/db) are hyperphagic, obese and diabetic, yet exhibit increased cholesterol absorption, reduced cholesterol synthesis, decreased biliary cholesterol, and resistance to cholethiasis. These observations suggest that in obesity the presence or absence of a functional leptin axis profoundly impacts cholesterol metabolism with respect to absorption, synthesis and hepatobiliary transport. The central hypothesis of this proposal is that hepatic leptin signaling maintains G5G8 and prevents reductions in hepatobiliary cholesterol transport by ER stress in diabesity.
The Aims are to 1) determine the role of hepatic leptin receptors on G5G8 abundance, activity and cholesterol metabolism in vivo, 2) determine the role of ER stress on G5G8 abundance in vivo and 3) determine the molecular mechanisms for regulation of G5G8 abundance by leptin, ER stress and the ISR. Leptin receptors will be selectively deleted from liver and brain to assess the role of this signaling pathway on G5G8 and cholesterol metabolism in obesity. The effects of leptin, ER stress and their interaction on G5G8 abundance will be determined in vivo and in vitro. The completion of these Aims will test our central hypothesis and elucidate the mechanisms by which the leptin axis modulates G5G8 abundance, hepatobiliary lipid transport and cholesterol metabolism in diabesity. Understanding the impact of this novel pathway on cholesterol metabolism will add insight to the effects of obesity on risk factors for cardiovascular disease.

Public Health Relevance

The ABCG5 ABCG8 sterol transporter is the principal mechanism by which the body opposes the accumulation of dietary cholesterol and other sterols from sources such as plants and shellfish. Little is known concerning the mechanisms that regulate its abundance and activity. This proposal addresses mechanisms that are responsible for reduced abundance and activity of G5G8 in mouse models of obesity and type 2 diabetes in order to gain insight into factors that contribute to the accumulation of cholesterol in obesity.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Haft, Carol R
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University of Kentucky
Schools of Pharmacy
United States
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Wang, Yuhuan; Su, Kai; Sabeva, Nadezhda S et al. (2015) GRP78 rescues the ABCG5 ABCG8 sterol transporter in db/db mice. Metabolism 64:1435-43
Wang, Yuhuan; Liu, Xiaoxi; Pijut, Sonja S et al. (2015) The combination of ezetimibe and ursodiol promotes fecal sterol excretion and reveals a G5G8-independent pathway for cholesterol elimination. J Lipid Res 56:810-20
Liu, Xiaoxi; Liu, Jingjing; Lester, Joshua D et al. (2015) ABCD2 identifies a subclass of peroxisomes in mouse adipose tissue. Biochem Biophys Res Commun 456:129-34
Liu, Xiaoxi; Liu, Jingjing; Liang, Shuang et al. (2014) ABCD2 alters peroxisome proliferator-activated receptor α signaling in vitro, but does not impair responses to fenofibrate therapy in a mouse model of diet-induced obesity. Mol Pharmacol 86:505-13
Su, Kai; Sabeva, Nadezhda S; Wang, Yuhuan et al. (2014) Acceleration of biliary cholesterol secretion restores glycemic control and alleviates hypertriglyceridemia in obese db/db mice. Arterioscler Thromb Vasc Biol 34:26-33
Jiang, Erlie; Perrard, Xiaoyuan Dai; Yang, Donglin et al. (2014) Essential role of CD11a in CD8+ T-cell accumulation and activation in adipose tissue. Arterioscler Thromb Vasc Biol 34:34-43
Meyer, Jason M; Graf, Gregory A; van der Westhuyzen, Deneys R (2013) New developments in selective cholesteryl ester uptake. Curr Opin Lipidol 24:386-92
Su, Kai; Sabeva, Nadezhda S; Liu, Jingjing et al. (2012) The ABCG5 ABCG8 sterol transporter opposes the development of fatty liver disease and loss of glycemic control independently of phytosterol accumulation. J Biol Chem 287:28564-75
Liu, Jingjing; Liang, Shuang; Liu, Xiaoxi et al. (2012) The absence of ABCD2 sensitizes mice to disruptions in lipid metabolism by dietary erucic acid. J Lipid Res 53:1071-9
Sabeva, Nadezhda S; McPhaul, Christopher M; Li, Xiangan et al. (2011) Phytosterols differentially influence ABC transporter expression, cholesterol efflux and inflammatory cytokine secretion in macrophage foam cells. J Nutr Biochem 22:777-83

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