The biochemistry of hypo- and hyperlipidemic fatty acid derivatives: metabolism and metabolic effects.

A selection of amphipatic hyper- and hypolipidemic fatty acid derivatives (fibrates, thia- and branched chain fatty acids) are reviewed. They are probably all ligands for the peroxisome proliferation activation receptor (PPARalpha) which has a low selectivity for its ligands. These compounds give hyper- or hypolipidemic responses depending on their ability to inhibit or stimulate mitochondrial fatty acid oxidation in the liver. The hypolipidemic response is explained by the following metabolic effects: Lipoprotein lipase is induced in liver where it is normally not expressed. Apolipoprotein CIII is downregulated. These two effects in liver lead to a facilitated (re)uptake of chylomicrons and VLDL, thus creating a direct transport of fatty acids from the gut to the liver. Fatty acid metabolizing enzymes in the liver (CPT-I and II, peroxisomal and mitochondrial beta-oxidation enzymes, enzymes of ketogenesis, and omega-oxidation enzymes) are induced and create an increased capacity for fatty acid oxidation. The increased oxidation of fatty acids "drains" fatty acids from the body, reduces VLDL formation, and ultimately explains the antiadiposity and improved insulin sensitivity observed after administration of peroxisome proliferators.