Clofibrate causes an upregulation of PPAR-α target genes but does not alter expression of SREBP target genes in liver and adipose tissue of pigs

Abstract

This study investigated the effect of clofibrate treatment on expression of target genes of peroxisome proliferator-activated receptor (PPAR)-alpha and various genes of the lipid metabolism in liver and adipose tissue of pigs. An experiment with 18 pigs was performed in which pigs were fed either a control diet or the same diet supplemented with 5 g clofibrate/kg for 28 days. Pigs treated with clofibrate had heavier livers, moderately increased mRNA concentrations of various PPAR-alpha target genes in liver and adipose tissue, a higher concentration of 3-hydroxybutyrate, and markedly lower concentrations of triglycerides and cholesterol in plasma and lipoproteins than control pigs (P < 0.05). mRNA concentrations of sterol regulatory element-binding proteins (SREBP)-1 and -2, insulin-induced genes (Insig)-1 and Insig-2, and the SREBP target genes acetyl-CoA carboxylase, 3-methyl-3-hydroxyglutaryl-CoA reductase, and low-density lipoprotein receptor in liver and adipose tissue and mRNA concentrations of apolipoproteins A-I, A-II, and C-III in the liver were not different between both groups of pigs. In conclusion, this study shows that clofibrate treatment activates PPAR-alpha in liver and adipose tissue and has a strong hypotriglyceridemic and hypocholesterolemic effect in pigs. The finding that mRNA concentrations of some proteins responsible for the hypolipidemic action of fibrates in humans were not altered suggests that there were certain differences in the mode of action compared with humans. It is also shown that PPAR-alpha activation by clofibrate does not affect hepatic expression of SREBP target genes involved in synthesis of triglycerides and cholesterol homeostasis in liver and adipose tissue of pigs.

Deletion of angiotensin II type I receptor reduces hepatic steatosis

“…Whereas induction of PPARa was observed in AT1a À/À mice, the present study lacks the direct evidence that suppressive effect of AT1R blockade on hepatic steatosis is mediated by PPARa. In this connection, we examined b-hydroxybutyrate levels since it is documented that PPARa activation leads to stimulation of ketogenesis [37,38]. This yielded marked increase in serum b-hydroxybutyrate in AT1a À/À mice.…”

Carnitine synthesis and uptake into cells are stimulated by fasting in pigs as a model of nonproliferating species

“…For that reason, effects related to PPARα activation observed in rodents cannot be directly applied for nonproliferating species such as humans. We have recently shown that pigs have a similar mRNA concentration of PPARα in the liver as humans, which is approximately 10-fold lower than in rats [25]. Therefore, the pig may be a useful model to study biochemical effects induced by treatment with PPARα agonists.…”

Effect of ShanZha, a Chinese herbal product, on obesity and dyslipidemia in hamsters receiving high-fat diet

“…PPAR␣ mainly expresses in liver, heart, muscle, and kidney to regulate the genes involved in fatty acid uptake (fatty acid binding protein; FABP), ␤-oxidation (acyl-Co A oxidase) and -oxidation (cytochrome P450) in liver. PPAR␣ is the target of lipid-lowering drugs including fibrates, fenofibrate and clofibrate (Akbiyik et al, 2004;Luci et al, 2007).…”