Stimulation of cholesterol synthesis and hepatic lipogenesis in patients with severe malabsorption.

Patients with severe malabsorption have abnormal lipid metabolism with low plasma cholesterol and frequently high triglyceride (TG) levels. The mechanisms behind these abnormalities and the respective roles of malabsorption itself and of the parenteral nutrition given to these patients are unclear. We measured endogenous lipids synthesis (cholesterol synthesis and hepatic lipogenesis) and the expression (mRNA concentrations in circulating mononuclear cells) of regulatory genes of cholesterol metabolism in 10 control subjects and 22 patients with severe malabsorption receiving (n = 18) or weaned of parenteral nutrition (n = 4). Patients had low plasma cholesterol (P < 0.01) and raised TG (P < 0.05) levels. Both fractional and absolute cholesterol synthesis (P < 0.001) and hepatic lipogenesis (P < 0.01) were increased. These abnormalities are independent of parenteral nutrition since they were present in patients receiving or weaned of parenteral nutrition. No relation between hepatic lipogenesis and plasma TG levels was found, suggesting that other metabolic abnormalities participated in hypertriglyceridemia. HMG-CoA reductase and LDL receptor mRNA levels were decreased (P < 0.05) in patients on long-term parenteral nutrition. HMG-CoA reductase mRNAs were normal in weaned patients.Severe malabsorption induces large increases of cholesterol synthesis and hepatic lipogenesis independently of the presence of parenteral nutrition. These abnormalities are probably due to the malabsorption of bile acids.

Mechanisms of the triglyceride- and cholesterol-lowering effect of fenofibrate in hyperlipidemic type 2 diabetic patients.

In humans, the precise mechanisms of the hypolipidemic action of fenofibrate, a peroxisome proliferator-activated receptor-alpha 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)-alpha 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-alpha 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-alpha and ABCAI mRNA levels suggests that fenofibrate stimulated reverse cholesterol transport.