IMPACT OF ESSENTIAL FATTY-ACID DEFICIENCY ON HEPATIC STEROL-METABOLISM IN RATS

The major aim of the current investigation was to define whether essen tial fatty acid (EFA) deficiency modifies the intrahepatic metabolism and biliary output of sterols in rats. EFA-deficient diet caused an im poverishment in Linoleic, arachidonic, and docosahexaenoic acids, and a marked enrichment in the eicosatrienoic acid of the plasma, Liver, a nd hepatic microsomes. During a short term of biliary drainage, a sign ificant decline of the pool size of biliary sterols was noted in EFA-d eficient rats compared with control rats. To assess the biosynthesis o f biliary components, the common bile duct was cannulated and the pool size depleted (24 hours). Subsequently, a 6-hour bile collection disc losed a significant decrease (nmoles/min/g liver) in bile acids (4.8 /- 0.3 vs. 8.4 +/- 0.7, P < .005), cholesterol (0.26 +/- 0.01 vs. 0.34 +/- 0.02, P < .05), and phospholipids (1.49 +/- 0.11 vs. 2.82 +/- 0.3 2, P < .005) in EFA-deficient rats compared with controls (n = 6/group ). When cholesterogenesis was measured by the incorporation of [C-14]a cetate and (H2O)-H-3 into cholesterol, using liver slices, it was also found to be significantly (P < .001) reduced in EFA deficient rats, T he activity of hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase , the rate-limiting enzyme in cholesterol biosynthesis, was consistent ly lower (80%, P < .001) in EFA-deficient rats. In parallel experiment s, the direct measurement of microsomal acyl-CoA:cholesterol acyltrans ferase (ACAT) showed a decrease averaging 52% (P < .001). This is in s triking contrast to the elevated activity (157%, P < .005) of choleste rol 7 alpha-hydroxylase, the rate-limiting enzyme in bile acid biosynt hesis. Current experiments also suggest that the enzyme regulation inv olving phosphorylation and dephosphorylation is modified by EFA defici ency. Among the structural alterations observed in the morphology of h epatocytes in EFA-deficient rats, the lumen of bile canaliculi was red uced in size. These results underline the importance of EFA in the maj or mechanisms involved in the maintenance of hepatocyte sterol balance .