Dietary Fat Modulation of Hepatic Lipogenesis

Abraham, Samuel

Abstract

Our overall goal is to delineate the mechanisms whereby dietary fats markedly influence the rate of hepatic lipogenesis in adult animals. In this proposal we will limit our efforts to those long term dietary effects which are mediated through changes in enzyme amounts and are not merely short term allosteric modifications of enzyme activities.
Our specific aims are to (a) identify the active compound(s) derived from polyunsaturated fatty acids (PUFA) which we believe triggers the depression of hepatic lipogenesis, and (b) determine whether this active compound(s) acts either on the rates of synthesis or degradation of specific lipogenic enzymes (fatty acid synthetase and acetyl-CoA carboxylase) or on both. The hypothesis to be tested states that the liver produces compounds from linoleate, arachidonate, and Alpha-linolenate possibly through the action of lipoxygenase and related enzymes, which repress the synthesis of hepatic fatty acids in a tissue specific manner. These compounds act on the protein synthesizing systems responsible for both the synthesis and the degradation of the lipogenic enzymes in the liver and thereby depress lipogenesis. For this purpose both intact rats and mice as well as primary hepatocyte cultures derived from rat livers will be studied. The in vivo experiments will attempt to identify the structural features required for a dietary fatty acid to be effective as an inhibitor of this process by its influence on hepatic lipogenic enzyme content determined by rocket immunoelectrophoresis. Primary hepatocyte cultures will be used to test the lipogenic depressing capacity of various polyunsaturated fatty acids as well as products of the lipoxygenase pathway known to be produced from linoleate via arachidonate isolated from either the livers of intact animals or from hepatocyte cultures.