Most of the triacylglycerol (TAG) utilized for the assembly of very-low-density lipoprotein (VLDL) in the secretory apparatus of the hepatocyte is mobilized by lipolysis of the cytosolic TAG pool, followed by re-esterification. The lipases involved include arylacetamide deacetylase and/or triacylglycerol hydrolase. Some of the re-esterified products of lipolysis gain access to an apolipoprotein-B-rich VLDL precursor to form mature VLDL. Some, however, are returned to the cytosolic pool in a process that is stimulated by insulin and inhibited by microsomal triacylglycerol transfer protein (MTP). Phospholipids also contribute to VLDL TAG in a process which involves ADP-ribosylation factor-1 (ARF-1)-mediated activation of phospholipase D. The temporary storage of TAG in the liver, followed by its mobilization and secretion as VLDL, form part of a process by which the liver protects vulnerable body tissues from excess lipotoxic non-esterified ('free') fatty acids in the plasma.

Inclusion of the PPARalpha (peroxisome-proliferator-activated receptor alpha) activator WY 14,643 in the diet of normal mice stimulated the hepatic expression of not only genes of the fatty acid oxidation pathway, but also those of the de novo lipid synthetic pathways. Induction of fatty acid synthase mRNA by WY 14,643 was greater during the light phase of the diurnal cycle, when food intake was low and PPARalpha expression was high. Hepatic fatty acid pathway flux in vivo showed a similar pattern of increases. The abundance of mRNAs for genes involved in hepatic cholesterol synthesis was also increased by WY 14,643, but was associated with a decrease in cholesterogenic carbon flux. None of these changes were apparent in PPARalpha-null mice. Mice of both genotypes showed the expected decreases in 3-hydroxy-3-methylglutaryl-CoA reductase mRNA levels and cholesterol synthesis in response to an increase in dietary cholesterol. The increase in fatty acid synthesis due to WY 14,643 was not mediated by increased expression of SREBP-1c (sterol regulatory element binding protein-1c) mRNA, but by an increase in cleavage of the protein to the active form. An accompanying rise in stearoyl-CoA desaturase mRNA expression suggested that the increase in lipogenesis could have resulted from an alteration in membrane fatty acid composition that influenced SREBP activation.