Adipose MTP and FIT2 in the regulation of plasma lipids, obesity and atherosclerosis

点击翻译按钮获取中文摘要

ABSTRACT – PROJECT 1: High blood levels of apoB-containing lipoproteins (apoB-Lps) are risk factors for cardiovascular diseases. ApoB-Lp production requires microsomal triglyceride (TG) transfer protein (MTP). However, MTP’s role in adipose tissue, which does not produce apoB-Lps, is unknown. Fat storage-inducing transmembrane protein 2 (FIT2) is another TG-binding protein that is involved in lipid droplet (LD) formation in adipose tissue. While MTP functions in lumen of the endoplasmic reticulum (ER), FIT2 assists in the budding of LDs from the ER membrane towards cytosol. We hypothesize that these two TG binding proteins perform different functions that affect adipocyte biology, hepatic lipid metabolism, and atherosclerosis. We showed that adipose-specific MTP deficient (A-Mttp−/−) mice are resistant to diet- induced obesity, hepatosteatosis and atherosclerosis, but adipose FIT2 deficiency causes hepatosteatosis and inflammation. These contrasting phenotypes compel us to ask if MTP deficiency can ameliorate pathologies associated with FIT2 deficiency. Aim 1.1: Role of adipose MTP in hypertriglyceridemia, hepatosteatosis, and atherosclerosis. We showed that adipose MTP inhibits adipose TG lipase (ATGL). We will: 1) ask if adipose MTP also modulates other lipases beyond ATGL; 2) work with P2 and P3 to elucidate mechanisms for hypertriglyceridemia and reduced hepatosteatosis; and 3) collaborate with C1–C3 to explain why atherosclerosis is lower in A-Mttp−/− mice. These studies will uncover how MTP promotes adipose TG storage and obesity. We propose that inhibiting adipose-specific MTP function will reduce obesity and atherosclerosis. Aim 1.2: Role of MTP and FIT2 in adipose biology, hepatosteatosis, and atherosclerosis. Given the distinct roles and sites of action of MTP and FIT2 within adipocytes, we will study the effect of adipose-specific MTP and FIT2 deficiencies on whole-body metabolism, adipose lipolysis, and atherosclerosis, and ask if MTP deficiency ameliorates FIT2-associated pathology with help from C1–C3 and expertise from P2 and P3. Our studies will: 1) provide novel information on the roles of adipose MTP and FIT2 in adipose, liver, and vascular biology; 2) generate novel mouse models; 3) explain roles of MTP and FIT2 in metabolism, TG hydrolysis, and FA secretion and oxidation; and 4) define how adipose–liver crosstalk controls obesity, hypertriglyceridemia, hepatosteatosis, and atherosclerosis. Elucidating the mechanisms of apoB-Lps production depends on collaboration with P2. We will then work with P3 to: 1) study intravascular catabolism of apoB-Lps produced by adipose–specific MTP- and FIT2-deficient mice, 2) monitor apoB-Lp uptake by endothelial cells, and 3) elucidate pro- or anti-inflammatory responses in adipocytes and macrophages. Bioinformatics analyses of RNA-seq and single cell RNA-seq (by C1), Lp characterization (by C2), and atherosclerosis studies (by C3) will yield novel insights into how adipose-specific proteins regulate metabolism.