In Type 2 diabetes and metabolic syndrome, the liver appears to remain sensitive to the effects of insulin on lipogenesis and VLDL lipid and apoB secretion. In collaborative studies with Dr Accili, we showed that Ldlr- /- mice with genetically reduced levels of insulin receptors (IRs) in liver had decreased VLDL secretion and atherosclerosis. However, in mice with functioning LDLRs, restricted hepatic insulin signaling also led to diminished LDLR levels, indicating that the ability of insulin signaling to increase VLDL secretion is offset by an increase in LDLR levels. Recent studies have shown that the regulation of VLDL secretion and LDLR levels by insulin signaling may be mediated via effects on hepatic mTOR activity. Interestingly, mTOR signaling has been found to repress expression of Sort (a gene recently identified in GWAS of CAD and LDL levels), leading to increased VLDL triglyceride and apoB secretion. Preliminary results indicate that these effects may be mediated by mTOR-induced ER stress, leading to increased expression of ATF3, a transcriptional repressor of Sort. In contrast, the levels of LDLR appear to be regulated by a distinctive pathway downstream of mTOR that leads to decreased expression of Pcsk9 and a post-transcriptional increase in LDLR. The proposed studies will test the hypothesis that hepatic mTOR signaling acts as a central hub integrating signals from insulin and nutritional factors to regulate VLDL secretion and LDLR levels. This hypothesis will be tested using recently available mice with liver-specific knock-outs of key molecules regulating hepatic mTOR activity i.e. Li-TsclKO (increased mTORl activity) and Li-RapKO mice (reduced mTORl activity). With Drs Accili and Tabas, we will seek to show that genetic manipulations of insulin signaling that affect VLDL secretion and LDLR act upstream of mTOR, while ER stress, ATF3 and Sort act downstream of mTOR to regulate VLDL apoB and lipid secretion. With Dr Tabas, we will analyze liver samples from obese and lean subjects to determine if similar regulation of Sort occurs in humans. These studies should provide new insights into the regulation of VLDL secretion and LDLR levels in subjects with obesity and hyperinsulinemia.

Public Health Relevance

The dyslipidemia of Type 2 diabetes and metabolic syndrome is characterized by excessive production of VLDL but relatively normal levels of LDL cholesterol. However, the underiying mechanisms have remained pooriy understood. The proposed studies should provide new insights into the regulation of VLDL secretion and LDLR levels in these conditions.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
2P01HL087123-06A1
Application #
8460253
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2012-12-01
Budget End
2013-11-30
Support Year
6
Fiscal Year
2013
Total Cost
$151,835
Indirect Cost
$56,938
Name
Columbia University (N.Y.)
Department
Type
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Westerterp, Marit; Wang, Nan; Tall, Alan R (2016) High-Density Lipoproteins, Endothelial Function, and Mendelian Randomization. Circ Res 119:13-5
Cochran, Blake J; Hou, Liming; Manavalan, Anil Paul Chirackal et al. (2016) Impact of Perturbed Pancreatic β-Cell Cholesterol Homeostasis on Adipose Tissue and Skeletal Muscle Metabolism. Diabetes 65:3610-3620
Tabas, Ira (2016) Heart disease: Death-defying plaque cells. Nature 536:32-3
Hsieh, Joanne; Koseki, Masahiro; Molusky, Matthew M et al. (2016) TTC39B deficiency stabilizes LXR reducing both atherosclerosis and steatohepatitis. Nature 535:303-7
Ozcan, L; Tabas, I (2016) Calcium signalling and ER stress in insulin resistance and atherosclerosis. J Intern Med 280:457-464
Kim-Muller, Ja Young; Kim, Young Jung R; Fan, Jason et al. (2016) FoxO1 Deacetylation Decreases Fatty Acid Oxidation in β-Cells and Sustains Insulin Secretion in Diabetes. J Biol Chem 291:10162-72
Ozcan, Lale; Ghorpade, Devram S; Zheng, Ze et al. (2016) Hepatocyte DACH1 Is Increased in Obesity via Nuclear Exclusion of HDAC4 and Promotes Hepatic Insulin Resistance. Cell Rep 15:2214-25
Fredman, Gabrielle; Hellmann, Jason; Proto, Jonathan D et al. (2016) An imbalance between specialized pro-resolving lipid mediators and pro-inflammatory leukotrienes promotes instability of atherosclerotic plaques. Nat Commun 7:12859
Libby, Peter; Bornfeldt, Karin E; Tall, Alan R (2016) Atherosclerosis: Successes, Surprises, and Future Challenges. Circ Res 118:531-4
Westerterp, Marit; Tsuchiya, Kyoichiro; Tattersall, Ian W et al. (2016) Deficiency of ATP-Binding Cassette Transporters A1 and G1 in Endothelial Cells Accelerates Atherosclerosis in Mice. Arterioscler Thromb Vasc Biol 36:1328-37

Showing the most recent 10 out of 81 publications