Fatty acids as determinants of triglyceride and cholesteryl ester synthesis by isolated hepatocytes: Kinetics as a function of various fatty acids

Triglyceride synthesis by hepatocytes is currently thought to be the rate- limiting step for lipoprotein formation. In order to determine whether triglyceride and cholesteryl ester syntheses in hepatocytes are sensitive to physiological fluctuations of serum fatty acids, the fatty acid dependence of these pathways was examined. Uptake of various fatty acids and incorporation into triglyceride and cholesteryl esters were studied in isolated rat hepatocytes. Rates were determined under conditions of linear incorporation and related to the concentrations of total and unbound fatty acid in a mixture of fatty acids and albumin. The findings were: pathways for triglyceride and cholesteryl ester synthesis saturated at unbound fatty acid concentrations (or fatty acid albumin ratios) within the range of serum values and thus would be acutely modulated by fluctuations in serum fatty acids. Addition of cholesterol to the medium increased cellular cholesterol, but did not alter rates of cholesterol esterification, suggesting that endogenous cholesterol synthesis provided the needed substrate. Oleate, palmitate, and linoleate were comparable in their saturation kinetics and ability to support triglyceride and cholesteryl ester synthesis. Consequently, their binding affinity for serum albumin would determine their lipid-incorporation rates. On this basis, in humans, oleate would yield the lowest rates as it has the lowest unbound fatty acid at each fatty acid- albumin ratio. Stearate, in contrast to the other fatty acids, was poorly esterified into neutral lipids by hepatocytes. Poor hepatic metabolism of stearate most likely explains previous findings of a hypocholesteremic effect of diets high in stearate as compared to other saturated fatty acids. The findings are generally consistent with an important role of serum fatty acid- albumin ratios in acutely modulating lipid and consequently lipoprotein synthesis by hepatocytes.