Transcriptional modulation of hepatic lipoprotein assembly and secretion : coordinate regulation of the liver-fatty acid binding protein and microsomal triglyceride transfer protein genes

Hepatic production of apolipoprotein (apo) B-containing lipoproteins provides a means to transport essential lipids and fat-soluble nutrients to peripheral tissues for utilization and storage. Liver-fatty acid binding protein (L-FABP) and microsomal triglyceride transfer protein (MTP) bind fatty acids and glycerolipids, respectively and facilitate their transfer into the VLDL assembly and secretion pathway. Sequence analysis reveals that the proximal promoter regions of L-FABP and MTP contain similar DR1 elements, suggesting the transcription of these two genes may be coordinately regulated. The inability of L35 hepatoma cells to express L-FABP and MTP was attributed to transcriptional repression via binding of the orphan nuclear receptor chicken ovalbumin upstream promoter transcription factor II (COUP-TFII) to the proximal DR1 elements in both promoters. The high expression of L-FABP and MTP by FAO hepatoma cells correlated with occupation of the proximal DR1 elements by a heterodimeric complex consisting of the fatty acid activated nuclear receptors peroxisomal proliferator activated receptor a (PPARa) and retinoid X receptor a (RXRa). Treatment of L35 cells with PPARa and RXRa agonists induced the transcription and expression of both genes via their DR1 elements, and restored the ability of L35 cells to secrete apo B. This was associated with coordinate alterations in the relative expression levels of the DR1-associated factors, as well as alteration of complexes occupying the DR1 elements. Expression levels of the coactivator peroxisome proliferator-activated receptor g coactivator-1b (PGC-1b) correlates with L-FABP and MTP expression in both hepatoma cells and in the liver. RNAi- mediated reduction in the cellular content of PGC-1b inhibited the PPARa-RXRa agonist induction of both genes in FAO cells. Adenoviral over-expression of PGC-1b induced both L-FABP and MTP mRNA levels in a manner dependent upon PPARa-RXRa association with the proximal DR1 regions. The relative cellular concentrations of PPARa, RXRa and PGC-1b (increased in FAO cells) relative to COUP-TFII (increased in L35 cells) determines whether the activation-competent PPARa-RXRa complex or repressive COUP-TFII complex occupies the proximal DR1 elements of both the L-FABP and MTP promoters; in turn, determining the relative rates of transcription of both genes, allowing the liver to efficiently utilize fatty acids for VLDL assembly and secretio