Regulation of Hepatic Cholesterol Metabolism in the Rat in Vivo: Effect of a Synthetic Fat-free Diet on Sterol Synthesis and Low-density Lipoprotein Transport

A synthetic fat-free diet, previously shown to decrease hepatic cholesterol synthesis, was utilized to manipulate cholesterol balance in vivo in female Sprague-Dawley rats. A significant 65% decrease of hepatic cholesterol synthesis compared to controls was shown after 1 week of treatment, which remained constant during the following 3 weeks. The inhibitory effect of the diet was completely abolished by cholestyramine supplementation. At week 3 of the experimental diet, bile acid synthesis was reduced by 63%, this reduction being correlated with decreased recycling frequency of the bile acid pool. Hepatic clearance of low-density lipoprotein (LDL) was slightly decreased, with no changes in plasma cholesterol, hepatic LDL-cholesterol uptake and whole body LDL-cholesterol production. When cholesterol and saturated fatty acids were supplemented to the diets in the attempt to disclose alteration in LDL transport, LDL clearance was unaffected; plasma LDL-cholesterol and hepatic LDL-cholesterol uptake were increased, as a consequence of increased LDL-cholesterol production. On the other hand, hepatic cholesterol synthesis was further suppressed; bile acid synthesis was increased by cholesterol supplementation in the fat-free group, even if to subnormal levels. These findings suggest that: (1) bile acid synthesis is decreased by feeding a synthetic fat-free diet, probably due to slower recirculation of bile acids along the entero-hepatic axis in conditions of reduced functional need; (2) consequently, a significant reduction of hepatic cholesterol synthesis is observed with no changes in LDL-cholesterol uptake; (3) further supplementation of dietary cholesterol and saturated fats is compensated for by changes in the rates of cholesterol and bile acid synthesis, but not of LDL transport. The data confirm the existence of independent regulation for hepatic sterol synthesis and LDL transport in this species.