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Regulatory Effects of HMG CoA Reductase Inhibitor and Fish Oils on Apolipoprotein B-100 Kinetics in Insulin-Resistant Obese Male Subjects With Dyslipidemia
1. Dick C. Chan1, 
2. Gerald F. Watts1, 
3. P. Hugh R. Barrett1,
4. Lawrence J. Beilin1, 
5. Trevor G. Redgrave2 and 
6. Trevor A. Mori1
+Author Affiliations
1. 1Department of Medicine, University of WesternAustralia and the Western Australian Institute for Medical Research, Crawley, Western Australia
2. 2Department of Physiology, University of Western Australia, Crawley, Western Australia
 
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Abstract
Hepatic accumulation of lipid substrates perturbs apolipoproteinB-100 (apoB) metabolism in insulin-resistant, obese subjects and mayaccount for increased risk of cardiovascular disease. In a placebo-controlled trial, we examined the independent and combined effects of decreasing cholesterol synthesis with atorvastatin (40 mg/day) and triglyceride synthesis with fish oils (4 g/day) on apoB kinetics. The subjects were 48 viscerally obese, insulin-resistant men with dyslipidemia who were studied in a fasted state. We found thatatorvastatin significantly decreased plasma apoB-containing lipoproteins (P < 0.001, main effect) through increases in the fractional catabolic rate (FCR) of VLDL-, IDL-, and LDL-apoB (P < 0.01). Fish oils significantly decreased plasma levels of triglycerides and VLDL-apoB (P < 0.001), decreased the VLDL-apoB secretion rate (P < 0.01), but increased the conversion of VLDL to LDL (P <0.001). Compared with placebo, combined treatment with atorvastatin and fish oils decreased VLDL-apoB secretion (P < 0.03) and increased the FCR of apoB in each lipoprotein fraction (P < 0.03) and the percent conversion of VLDL to LDL (P < 0.05). None of the treatments altered insulin resistance. In conclusion, in visceral obesity, atorvastatin increased hepatic clearance of allapoB-containing lipoproteins, whereas fish oils decreased hepatic secretion of VLDL-apoB. The differential effects of atorvastatin and fish oils on apoB kinetics support their combined use in correcting defective apoB metabolism in obese, insulin-resistant subjects.
Visceral obesity is frequently associated with insulin resistance, which in turn is causally related to dyslipoproteinemia and increased riskof type 2 diabetes and cardiovascular disease (CVD) (1–3). Insulin resistance perturbs the metabolism of lipoproteins containing apolipoprotein B-100 (apoB), including VLDL, intermediate-density lipoprotein (IDL), and LDL. These abnormalities may account for the increased incidence of CVD in subjects with insulin resistance and type 2 diabetes (2,4).
Hepatic insulin resistance, involving both thediminished ability of insulin to suppress hepatic glucose production and increased lipogenesis, may ultimately be a consequence of adipose tissue insulin resistance that increases fatty acid flux to the liver (5). Increased fatty acid released from adipose tissue may also partly account for impaired uptake of glucose by skeletal muscle. Both hepatic and peripheral insulin resistance may resultfrom impaired insulin receptor signaling pathways involving decreased phosphatidylinositide 3-kinase activity (6). In visceral obesity, insulin resistance increases hepatic apoB secretion by several mechanisms: increased fatty acid flux to the liver, resistance to a direct inhibitory effect of insulin on apoB secretion, increased expression of microsomal triglyceride transfer protein, and increasedde novo lipogenesis (2). Increased lipogenesis may also be caused by overexpression of sterol regulatory element binding protein-1c (SREBP-1c) (1). Chronic hyperinsulinemia also channels hepatic fatty acids and storage triglyceride pools into a secretory pool that directly impacts VLDL secretion (7). These metabolic sequelae of insulin resistance support the notion that the availability of core...
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