Grants and Contracts Details
Description
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.
Status | Finished |
---|---|
Effective start/end date | 7/1/09 → 5/31/14 |
Funding
- National Institute Diabetes & Digestive & Kidney: $1,311,232.00
Fingerprint
Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.