In humans, the precise mechanisms of the hypolipidemic action of fenofibrate, a peroxisome proliferator-activated receptor-␣ agonist, remain unclear. To gain insight on these mechanisms, we measured plasma lipids levels, lipids synthesis (hepatic de novo lipogenesis and cholesterol synthesis), and mRNA concentrations in circulating mononuclear cells (RT-PCR) of hydroxymethylglutaryl (HMG)-CoA reductase, LDL receptor, LDL receptor-related protein (LRP), scavenger receptor class B type I (SR-BI), ABCAI, and liver X receptor (LXR)-␣ in 10 control subjects and 9 hyperlipidemic type 2 diabetic patients. Type 2 diabetic subjects were studied before and after 4 months of fenofibrate administration. Fenofibrate decreased plasma triglycerides (P < 0.01) and total cholesterol (P < 0.05) concentrations and slightly increased HDL cholesterol (P < 0.05). Hepatic lipogenesis, largely enhanced in diabetic subjects (16.1 ؎ 2.1 vs. 7.5 ؎ 1.6% in control subjects, P < 0.01), was decreased by fenofibrate (9.8 ؎ 1.5%, P < 0.01). Fractional cholesterol synthesis was normal in diabetic subjects (3.5 ؎ 0.4 vs. 3.3 ؎ 0.5% in control subjects) and was unchanged by fenofibrate (3.5 ؎ 0.5%). Absolute cholesterol synthesis was, however, increased in diabetic subjects before and after fenofibrate (P < 0.05 vs. control subjects). HMG-CoA reductase, LDL receptor, LRP, and SR-BI mRNA concentrations were not different in type 2 diabetic and control subjects and were unchanged by fenofibrate. LXR-␣ mRNA levels were increased (P < 0.05) by fenofibrate. ABCAI mRNA concentrations, which were decreased in diabetic subjects (P < 0.05) before fenofibrate, were increased (P < 0.05) by fenofibrate to values comparable to those of control subjects. The plasma triglyceride-lowering effect of fenofibrate is explained in part by a decrease in hepatic lipogenesis, the moderate fall in total plasma cholesterol is not explained by a reduction of whole-body cholesterol synthesis, and the increase in LXR-␣ and ABCAI mRNA levels suggests that fenofibrate stimulated reverse cholesterol transport. Diabetes 51:3486 -3491, 2002

The beneficial effects of the HC diet on glucose tolerance and plasma cholesterol concentrations without increases in triacylglycerol show that this diet had favorable effects on both insulin sensitivity and the plasma lipid profile.

To determine the effect of hyperthyroidism on hepatic lipogenesis and cholesterol synthesis we measured these metabolic pathways (deuterated water method) in euthyroid and hyperthyroid subjects investigated in the postabsorptive state. Hyperthyroid patients had increased concentrations of glucose (P < 0.05), insulin (P < 0.05), nonesterified fatty acids (P < 0.01), and triglycerides (P < 0.05) and decreased levels of plasma cholesterol (P < 0.01). The contribution of hepatic lipogenesis to plasma triglycerides was largely increased in hyperthyroid subjects (23.0 +/- 1.8% vs. 7.5 +/- 0.2%; P < 0.001), whereas the fractional synthetic rate of cholesterol was moderately higher (5.0 +/- 0.8% vs. 3.3 +/- 0.2%; P < 0.05). mRNA levels of beta-hydroxy-beta-methyl glutaryl-coenzyme A reductase, measured in circulating mononuclear cells, were increased (P < 0.05), whereas those of low density lipoprotein (LDL) receptor and LDL receptor-related protein were unchanged. Sterol responsive element binding protein-1c mRNAs were undetectable in mononuclear cells from both groups of subjects. The large stimulation of hepatic lipogenesis in hyperthyroid patients is probably explained by both a direct action of thyroid hormones and the increase in insulin. It could contribute to their moderate rise in triglycerides levels. The decreased plasma cholesterol level is observed despite an enhanced synthetic rate and is thus related to an increased clearance rate. The lack of increased expression of LDL receptor and LDL receptor-related protein suggests that other receptors are implicated.