Increased secretion of apoliprotein B (apoB)-lipoproteins (Lps) characterizes both animal models and humans with dyslipidemia accompanying IR and type 2 diabetes mellitus (T2DM). The goal of the proposed studies is to provide new and unique insights into the integrated roles that hepatic fatty acids (FA) and triglycerides (TG), plasma FA, and hepatic insulin signaling play in determining both the secretion of apoB- Lps and development of hepatic steatosis. Of particular interest is the question: Why does hepatic steatosis occurs despite increased secretion of apoB-Lps in animals and people with IR. Our first hypothesis focuses on the roles of hepatic FA and TG on the assembly and secretion of apoB-Lps. The 3 aims under Hypothesis 1, test our belief that increased hepatic TG, from any source, is a potent determinant of the quantity of TG added to each apoB-Lp, but has only a minimal to modest effect on the number of particles secreted. We believe that the inability of increased hepatic TG to adequately stimulate secretion of increased numbers of apoB-Lps predisposes to steatosis. By contrast, we propose that increased uptake of circulating FA by the liver potently stimulates the secretion of increased numbers of apoB-Lps, potentially protecting against steatosis while possibly worsening the dyslipidemia. Importantly, we believe that FA- mediated stimulation of apoB-Lp secretion is independent of its incorporation into a common TG pool, and that FA from hepatic DNS do not effectively stimulate apoB-Lp secretion. The second hypothesis focuses on insulin-mediated degradation of apoB. The 4 aims under Hypothesis 2 focus on whether the effects of hepatic insulin signaling on apoB-Lp secretion will be modulated by hepatic TG and by FA from the circulation. We believe that increased hepatic TG will reduce insulin-mediated post-ER degradation of apoB while increased hepatic uptake of FA will reduce both insulin-mediated ER and post-ER degradation of apoB. Reduced hepatic insulin signaling will cause more apoB secretion and less hepatic TG, irrespective of prevailing hepatic synthesis of TG or FA flux. Finally, Hypothesis 3 and the aims that follow will focus on the possibility that ER stress, mediated by high fat diets or insulin resistance, alters apoB secretion. If ER stress partially inhibits apoB-Lp secretion that would predispose to steatosis. All of these studies will lead to a clearer understanding of, and new approaches to the treatment of dyslipidemia and hepatic steatosis. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL055638-11A1
Application #
7258570
Study Section
Integrative Nutrition and Metabolic Processes Study Section (INMP)
Program Officer
Ershow, Abby
Project Start
1996-08-01
Project End
2012-03-31
Budget Start
2007-04-01
Budget End
2008-03-31
Support Year
11
Fiscal Year
2007
Total Cost
$402,500
Indirect Cost
Name
Columbia University (N.Y.)
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Munkacsi, Andrew B; Hammond, Natalie; Schneider, Remy T et al. (2017) Normalization of Hepatic Homeostasis in the Npc1nmf164 Mouse Model of Niemann-Pick Type C Disease Treated with the Histone Deacetylase Inhibitor Vorinostat. J Biol Chem 292:4395-4410
Blaner, William S; Gao, Madeleine A; Jiang, Hongfeng et al. (2017) Chronic alcohol consumption decreases brown adipose tissue mass and disrupts thermoregulation: a possible role for altered retinoid signaling. Sci Rep 7:43474
Conlon, Donna M; Thomas, Tiffany; Fedotova, Tatyana et al. (2016) Inhibition of apolipoprotein B synthesis stimulates endoplasmic reticulum autophagy that prevents steatosis. J Clin Invest 126:3852-3867
Reyes-Soffer, Gissette; Moon, Byoung; Hernandez-Ono, Antonio et al. (2016) Complex effects of inhibiting hepatic apolipoprotein B100 synthesis in humans. Sci Transl Med 8:323ra12
Liu, Jing; Hernandez-Ono, Antonio; Graham, Mark J et al. (2016) Type 1 Deiodinase Regulates ApoA-I Gene Expression and ApoA-I Synthesis Independent of Thyroid Hormone Signaling. Arterioscler Thromb Vasc Biol 36:1356-66
Ronsein, Graziella E; Reyes-Soffer, Gissette; He, Yi et al. (2016) Targeted Proteomics Identifies Paraoxonase/Arylesterase 1 (PON1) and Apolipoprotein Cs as Potential Risk Factors for Hypoalphalipoproteinemia in Diabetic Subjects Treated with Fenofibrate and Rosiglitazone. Mol Cell Proteomics 15:1083-93
Go, Gwang-Woong; Srivastava, Roshni; Hernandez-Ono, Antonio et al. (2014) The combined hyperlipidemia caused by impaired Wnt-LRP6 signaling is reversed by Wnt3a rescue. Cell Metab 19:209-20
Juárez-Rojas, Juan G; Reyes-Soffer, Gissette; Conlon, Donna et al. (2014) Autophagy and cardiometabolic risk factors. Rev Endocr Metab Disord 15:307-15
Lassman, Michael E; McAvoy, Thomas; Lee, Anita Y H et al. (2014) Practical immunoaffinity-enrichment LC-MS for measuring protein kinetics of low-abundance proteins. Clin Chem 60:1217-24
Zhou, Haihong; Castro-Perez, Jose; Lassman, Michael E et al. (2013) Measurement of apo(a) kinetics in human subjects using a microfluidic device with tandem mass spectrometry. Rapid Commun Mass Spectrom 27:1294-302

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