Mechanisms of hepatic very low-density lipoprotein overproduction in insulin resistance.
An important complication of insulin-resistant states, such as obesity and type 2 diabetes, is an atherogenic dyslipidemia profile characterized by hypertriglyceridemia, low plasma high-density lipoproteins (HDL) cholesterol and a small, dense low-density lipoprotein (LDL) particle profile. The physiological basis of this metabolic dyslipidemia appears to be hepatic overproduction of apoB-containing very low-density lipoprotein (VLDL) particles. This has focused attention on the mechanisms that regulate VLDL secretion in insulin-resistant states. Recent studies in animal models of insulin resistance, particularly the fructose-fed hamster, have enhanced our understanding of these mechanisms, and certain key factors have recently been identified that play important roles in hepatic insulin resistance and dysregulation of the VLDL secretory process. This review focuses on these recent developments as well as on the hypothesis that an interaction between enhanced flux of free fatty acids from peripheral tissues to liver, chronic up-regulation of de novo lipogenesis by hyperinsulinemia and attenuated insulin signaling in the liver may be critical to the VLDL overproduction state observed in insulin resistance. It should be noted that the focus of this review is on molecular mechanisms of the hypertriglyceridemic state associated with insulin resistance and not that observed in association with insulin deficiency (e.g., in streptozotocin-treated animals), which appears to have a different etiology and is related to a catabolic defect rather than secretory overproduction of triglyceride-rich lipoproteins.
Adeli
K
K
Division of Clinical Biochemistry, Department of Laboratory Medicine & Pathobiology, Hospital for Sick Children, University of Toeonto, Toronto, Ontario, Canada. k.adeli@utoronto.ca
Taghibiglou
C
C
Van Iderstine
S C
SC
Lewis
G F
GF
D000818:Animals; D001055:Apolipoproteins B / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D005230:Fatty Acids, Nonesterified / Q000096:biosynthesis; D015228:Hypertriglyceridemia / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D008079:Lipoproteins, VLDL / Q000096:biosynthesis*; D008099:Liver / Q000378:metabolism*; D023421:Models, Animal; D011972:Receptor, Insulin / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
D001055:Apolipoproteins B; D002352:Carrier Proteins; D005230:Fatty Acids, Nonesterified; D008079:Lipoproteins, VLDL; D011972:Receptor, Insulin