Peroxisome Proliferator-activated Receptor β/δ Regulates Very Low Density Lipoprotein Production and Catabolism in Mice on a Western Diet

Abstract

The results of recent studies using selective agonists for peroxisome proliferator-activated receptor ␤ (PPAR␤) suggest that this receptor may have a role in regulating levels of serum lipids in animal models of obesity and insulin resistance. To further examine this possibility, serum lipid profiles of mice lacking a functional PPAR␤ receptor were determined. PPAR␤-null mice maintained on either normal chow or a 10-week high fat (HF) diet, a condition that has been shown to induce insulin resistance and obesity in mice, have elevated levels of serum triglycerides primarily associated with very low density lipoprotein (VLDL) with no difference in either total cholesterol or phospholipids. Consistent with this finding, PPAR␤-null mice on a HF-diet were shown to have an increased rate of hepatic VLDL production as well as lowered lipoprotein lipase activity in serum compared with wild-type controls. The latter parallels an increase in the hepatic expression of the genes encoding angiopoietin-like proteins 3 and 4 in PPAR␤-null mice on a HF diet, both proteins of which have recently been shown to inhibit lipoprotein lipase (LPL) activity in vivo. Consistent with elevated VLDL production, a marked increase in plasma VLDL apoB48, -E, -AI, and -AII, as well as a sharp depletion of the hepatic lipid stores was also found in PPAR␤-null mice. In addition, PPAR␤-null mice on a HF diet were shown to have increased adiposity, despite lower total body weight. Together, these results indicate a clear role for PPAR␤ in regulating levels of serum triglycerides in mice on a high fat Western diet by modulating both VLDL production and LPL-mediated catabolism of VLDL-triglycerides and also suggest a potential therapeutic role for PPAR␤ in the improvement of serum lipids in the setting of metabolic syndrome.The peroxisome proliferator-activated receptors (PPARs) 1 are members of the nuclear hormone receptor superfamily.

Transcriptional profiling reveals divergent roles of PPARα and PPARβ/δ in regulation of gene expression in mouse liver

“…Confirming a previous report and in line with the plasma triglyceride-lowering effect of PPAR␤/␦ agonists in primates (1,36), plasma triglyceride levels were elevated in PPAR␤/␦Ϫ/Ϫ mice, at least in the fed state. In contrast, plasma total cholesterol was reduced in PPAR␤/␦Ϫ/Ϫ mice in the fasted state.…”

“…S1B). Surprisingly, a relatively large number of genes was downregulated during fasting in a 1 The online version of this article contains supplemental material. To examine to what extent PPAR␣ and PPAR␤/␦ govern the same genes, we created Venn diagrams showing the overlap in genes altered upon PPAR␣ and PPAR␤/␦ deletion.…”

“…In contrast, plasma total cholesterol was reduced in PPAR␤/␦Ϫ/Ϫ mice in the fasted state. Elevated plasma triglyceride levels in PPAR␤/␦Ϫ/Ϫ mice have been suggested to be related to a combination of increased VLDL production and decreased plasma triglyceride clearance, as evidenced by a decrease in postheparin LPL activity and increased hepatic expression of LPL inhibitors Angptl3 and Angptl4 (1). Based on the data presented here, it can be speculated that elevated plasma triglycerides may also be due to decreased expression of VLDL receptor Vldlr and/or changes in production of various apolipoproteins, including Apoa5, Apoa4, and Apoc1.…”

Disruption of CXC Motif Chemokine Ligand-14 in Mice Ameliorates Obesity-induced Insulin Resistance

“…Levels of serum cholesterol, serum, and hepatic triglyceride and serum FFAs were analyzed using the corresponding enzyme-based measurement kits (Wako). To determine hepatic triglyceride concentrations, liver fragments (100 mg) were homogenized in 1 ml of 0.1 M KCl, and lipids were extracted from the homogenate with chloroform:methanol (2:1, v/v) (29). An aliquot of the organic phase was collected, dried, and resuspended in isopropyl alcohol containing 1% Triton X-100.…”

Peroxisome Proliferator-Activated Receptor β/δ (PPAR β/δ) as a Potential Therapeutic Target for Dyslipidemia

“…In obese and diabetic db/db mice, administration of a PPAR / agonist modestly increased HDL particles, without affecting triglyceride levels (Leibowitz et al, 2000), whereas in a shorter treatment with GW501516 a reduction in plasma free fatty acids and triglyceride levels was observed in db/db mice, but not in mice exposed to a high fat diet (Tanaka et al, 2003). In mice, deletion of PPAR / led to enhanced LDL and triglyceride levels (Akiyama et al, 2004). It has been proposed that the increase in triglycerides observed in these PPAR / -null mice is caused by a combination of increased VLDL production and decreased plasma triglyceride clearance, as demonstrated by a decrease in postheparin LPL activity and increased hepatic expression of the LPL inhibitors Angptl3 and 4 (Akiyama et al, 2004).…”