No 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...

Peroxisome proliferator-activated receptor (PPAR) alpha is a nuclear receptor that is mainly expressed in tissues with a high degree of fatty acid oxidation such as liver, heart, and skeletal muscle. Unsaturated fatty acids, their derivatives, and fibrates activate PPARalpha. Male rats are more responsive to fibrates than female rats. We therefore wanted to investigate if there is a sex difference in PPARalpha expression. Male rats had higher levels of hepatic PPARalpha mRNA and protein than female rats. Fasting increased hepatic PPARalpha mRNA levels to a similar degree in both sexes. Gonadectomy of male rats decreased PPARalpha mRNA expression to similar levels as in intact and gonadectomized female rats. Hypophysectomy increased hepatic PPARalpha mRNA and protein levels. The increase in PPARalpha mRNA after hypophysectomy was more pronounced in females than in males. GH treatment decreased PPARalpha mRNA and protein levels, but the sex-differentiated secretory pattern of GH does not determine the sex-differentiated expression of PPARalpha. The expression of PPARalpha mRNA in heart or soleus muscle was not influenced by gender, gonadectomy, hypophysectomy, or GH treatment. In summary, pituitary-dependent hormones specifically regulate hepatic PPARalpha expression. Sex hormones regulate the sex difference in hepatic PPARalpha levels, but not via the sexually dimorphic GH secretory pattern.

It is known that bovine GH (bGH) transgenic mice have increased body mass, insulin resistance, and altered lipoprotein metabolism when fed a normal diet (ND). In this study, the effects of 8 wk of high-fat diet (HFD) were investigated in 6-month-old male bGH mice. Although littermate controls had unchanged energy intake, energy intake was higher in the bGH mice on a HFD than on a low-fat diet. Nevertheless, the bGH mice were resistant to diet-induced weight gain, and only in the bGH mice did the HFD result in increased energy expenditure. Glucose oxidation was higher in the bGH mice compared with littermate controls on both a HFD and ND. In addition, the bGH mice had 0.5 C higher body temperature throughout the day and increased hepatic uncoupling protein 2 expression; changes that were unaffected by the HFD. On a HFD, the effect of bGH overexpression on serum triglycerides and apolipoprotein B was opposite to that on a ND, resulting in higher serum concentrations of triglycerides and apolipoprotein B compared with littermate controls. Increased serum triglycerides were explained by decreased triglyceride clearance. The HFD led to diabetes only in the bGH mice. In conclusion, bGH transgenic mice were resistant to diet-induced obesity despite hyperphagia, possibly due to increased energy expenditure. On a HFD, bGH mice became dyslipidemic and diabetic and thereby more accurately reflect the metabolic situation in acromegalic patients.