Activation of Peroxisome Proliferator-activated Receptor α Increases the Expression and Activity of Microsomal Triglyceride Transfer Protein in the Liver

Abstract

Microsomal triglyceride transfer protein (MTP) is rate-limiting in the assembly and secretion of lipoproteins containing apolipoprotein (apo) B. Previously we demonstrated that Wy 14,643 (Wy), a peroxisome proliferator-activated receptor (PPAR) ␣ agonist, increases apoB-100 secretion despite decreased triglyceride synthesis. In this study, we sought to determine whether PPAR␣ activation increases MTP expression and activity. Treatment with Wy increased hepatic MTP expression and activity in rats and mice and increased MTP expression in primary cultures of rat and mouse hepatocytes. Addition of actinomycin D blocked this increase and the MTP promoter (؊136 to ؉67) containing a conserved DR1 element was activated by Wy, showing that PPAR␣ activates transcription of the gene. Wy did not affect MTP expression in the intestine or in cultured hepatocytes from PPAR␣-null mice. A retinoid X receptor agonist (9-cis-retinoic acid), but not a PPAR␥ agonist (rosiglitazone), increased MTP mRNA expression in cultured hepatocytes from both wild type and PPAR␣-null mice. In rat hepatocytes incubated with Wy, MTP mRNA levels increased between 6 and 24 h, and MTP protein expression and apoB-100 secretion increased between 24 and 72 h. In conclusion, PPAR␣ activation stimulates hepatic MTP expression via increased transcription of the Mtp gene. This effect is paralleled by a change in apoB-100 secretion, indicating that the effect of Wy on apoB-100 secretion is mediated by increased expression of MTP. The peroxisome proliferator-activated receptor (PPAR)1 ␣ is a nuclear receptor that controls the transcription of genes involved in several lipid metabolism pathways, such as ␤-oxidation and fatty acid uptake and transport, as well as lipoprotein production and clearance (1-3). PPAR␣ is expressed in tissues with a high degree of fatty acid catabolism, primarily liver, intestine, and skeletal muscle (1, 2, 4). PPAR␣ heterodimerizes with the retinoid X receptor ␣ (RXR␣), and this complex binds DR1 sequences that constitute PPAR response elements (for reviews, see Refs. 1, 2). The endogenous ligands for PPAR␣ are unsaturated fatty acids and eicosanoids, whereas hypolipidemic fibrates such as Wy 14,643 (Wy) are potent synthetic agonists (5). We recently found that PPAR␣ agonists increased apolipoprotein (apo) B-100 secretion 2-fold but did not change apoB-48 secretion (6). The increase occurred despite decreased triglyceride synthesis and unchanged apoB mRNA editing and could be explained by inhibition of the cotranslational degradation of apoB-100.Microsomal triglyceride transfer protein (MTP) catalyzes the transfer of neutral lipids to apoB and thus has a pivotal role in the assembly of apoB-containing lipoproteins (for reviews, see Refs. 7,8). The 97-kDa MTP protein that confers lipid transfer activity heterodimerizes with protein disulfide isomerase. Mutations in the Mtp gene cause abetalipoproteinemia, which is characterized by the inability to secrete apoB-containing lipoproteins (7,8). MTP influences apoB secretion through its eff...

Coordinate Transcriptional Repression of Liver Fatty Acid-binding Protein and Microsomal Triglyceride Transfer Protein Blocks Hepatic Very Low Density Lipoprotein Secretion without Hepatosteatosis

“…PPAR␣ and RXR␣ agonists have been shown to activate the transcription of L-FABP in hepatoma cells, an effect dependent on the DR1 site in the proximal promoter region (43). Treating wild type but not PPAR␣ knock-out mice with a PPAR␣ agonist increased hepatic expression of MTP (54). These and additional findings obtained from studies examining transcriptional regulation of genes involved in fatty acid metabolism (55)(56)(57)(58) support the proposal that PPAR␣-RXR␣ and COUP-TFII compete with each other for binding to DR1 promoter elements.…”

“…Substrate-driven "feed-forward" transcriptional regulation is a common mechanism allowing changes in gene expression to occur concomitantly with variations in metabolic needs (52). Because fatty acids also can activate PPAR␣-dependent gene transcription of L-FABP (53) and MTP (54), fatty acid flux to the liver both induces the enzymes controlling VLDL assembly/secretion as well as providing lipogenic substrate.…”

Fenofibrate Reduces Postprandial Hypertriglyceridemia in CD36 Knockout Mice

“…It has been reported that PPAR-agonists increase MTP expression and apoB secretion in rodent liver but not in the intestine in spite of decreased plasma TG levels 27) . We found that MTP expression was not affected by fenofibrate in the intestine of CD36KO mice in the postprandial state, which also contributes to the idea that regulation of the production of apoB-containing lipoproteins in the intestine might be different from the liver.…”

Effects of insulin resistance and hepatic lipid accumulation on hepatic mRNA expression levels of apoB, MTP and L-FABP in non-alcoholic fatty liver disease

“…HNF4α binds long chain fatty acyl-CoA and this binding stimulates its transcriptional activity (16,17). PPARα, which regulates the expression of a number of genes critical for lipid and lipoprotein metabolism, is known to transactivate MTP expression in rat liver and cultured hepatocytes (18,19). PPARα is also responsible for the induction of L-FABP in hepatocytes in response to HMG-CoA (20).…”