Regulation of plasma triglycerides in insulin resistance and diabetes.
Increased plasma levels of triglycerides (TG) in very low density lipoproteins (VLDL) are not only common characteristics of the dyslipidemia associated with insulin resistance and type 2 diabetes mellitus (T2DM) but are the central pathophysiologic feature of the abnormal lipid profile. Overproduction of VLDL leads to increased plasma levels of TG which, via an exchange process mediated by cholesterol ester transfer protein (CETP), results in low levels of high density lipoprotein (HDL) cholesterol and apolipoprotein A-I, and the generation of small, dense, cholesterol ester depleted low density lipoproteins (LDL). Increased assembly and secretion of VLDL by the liver results from the complex, post-transcriptional regulation of apolipoprotein B (apoB) metabolism in the liver. In the presence of low levels of hepatic TG and cholesterol, much of the constitutively synthesized apoB is degraded by both proteasomal and non-proteasomal pathways. When excess TG, and to a lesser extent, cholesterol, are present, and in the presence of active microsomal triglycerides transfer protein, apoB is targeted for secretion. The major sources of TG in the liver: uptake of fatty acids (FA) released by lipolysis of adipose tissue TG, uptake of TGFA in VLDL and chylomicrons remnants, and hepatic de novo lipogenesis (the synthesis of FA from glucose) are all abnormally increased in insulin resistance. Treatment of the dyslipidemia in insulin resistant individuals and patients with T2DM has been successful in reducing cardiovascular disease; LDL cholesterol, TG, and HDL cholesterol are all appropriate targets for therapy when diet, exercise, and weight loss do not achieve goals.
Ginsberg
Henry N
HN
College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA. hng1@columbia.edu
Zhang
Yuan-Li
YL
Hernandez-Ono
Antonio
A
D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D016632:Apolipoprotein A-I / Q000378:metabolism; D001055:Apolipoproteins B / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D002914:Chylomicrons / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood*; D005227:Fatty Acids / Q000378:metabolism; D006801:Humans; D007333:Insulin Resistance; D050356:Lipid Metabolism; D008074:Lipoproteins / Q000378:metabolism; D008075:Lipoproteins, HDL / Q000378:metabolism; D008079:Lipoproteins, VLDL / Q000737:chemistry; D008099:Liver / Q000378:metabolism; D008954:Models, Biological; D014280:Triglycerides / Q000097:blood*
D016632:Apolipoprotein A-I; D001055:Apolipoproteins B; D002914:Chylomicrons; D005227:Fatty Acids; D008074:Lipoproteins; D008075:Lipoproteins, HDL; D008079:Lipoproteins, VLDL; D014280:Triglycerides; D002784:Cholesterol