Activation of peroxisome proliferator-activated receptor-α (PPARα) suppresses postprandial lipidemia through fatty acid oxidation in enterocytes

Abstract

Activation of peroxisome proliferator-activated receptor (PPAR)-α which regulates lipid metabolism in peripheral tissues such as the liver and skeletal muscle, decreases circulating lipid levels, thus improving hyperlipidemia under fasting conditions. Recently, postprandial serum lipid levels have been found to correlate more closely to cardiovascular diseases than fasting levels, although fasting hyperlipidemia is considered an important risk of cardiovascular diseases. However, the effect of PPARα activation on postprandial lipidemia has not been clarified. In this study, we examined the effects of PPARα activation in enterocytes on lipid secretion and postprandial lipidemia. In Caco-2 enterocytes, bezafibrate, a potent PPARα agonist, increased mRNA expression levels of fatty acid oxidation-related genes, such as acyl-CoA oxidase, carnitine palmitoyl transferase, and acyl-CoA synthase, and oxygen consumption rate (OCR) and suppressed secretion levels of both triglycerides and apolipoprotein B into the basolateral side. In vivo experiments revealed that feeding high-fat-diet containing bezafibrate increased mRNA expression levels of fatty acid oxidation-related genes and production of CO(2) and acid soluble metabolites in enterocytes. Moreover, bezafibrate treatment suppressed postprandial lipidemia after oral administration of olive oil to the mice. These findings indicate that PPARα activation suppresses postprandial lipidemia through enhancement of fatty acid oxidation in enterocytes, suggesting that intestinal lipid metabolism regulated by PPARα activity is a novel target of PPARα agonist for decreasing circulating levels of lipids under postprandial conditions.

DHA attenuates postprandial hyperlipidemia via activating PPARα in intestinal epithelial cells

“…For luciferase assays using a PPAR full-length (Clone 12G10; Monosan, Uden, The Netherlands), affi nity-purifi ed anti-apoB (Rockland, Gilbertsville, PA), and horseradish peroxidase (HRP)-conjugated anti-goat IgG (Promega) as the capture, primary, and secondary antibodies, respectively. Details of these procedures have been previously described ( 15 ). HRP activity was detected using a 3,3 ′ ,5,5 ′ -tetramethylbenzidine peroxidase substrate (KPL, Gaithersburg, MD).…”

“…FA oxidation with isolated intestinal epithelial cells and hepatocytes was analyzed as previously described ( 15,25 ). Briefl y, collected intestinal epithelial cells and hepatocytes were washed with 1% FBS/DMEM three times and used for experiments.…”

Lauric Acid Beneficially Modulates Apolipoprotein Secretion and Enhances Fatty Acid Oxidation via PPARα-dependent Pathways in Cultured Rat Hepatocytes

“…There are reports that medium chain fatty acids are natural ligands for PPAR, 45 and PPARα activation up-regulates fatty acid oxidation-related genes, such as acyl CoA oxidase and carnitine palmitoyl transferase I, which suppresses postprandial lipidemia and lipid accumulation in enterocytes. 50, 51 Our study clearly proved that lauric acid may act as ligand for PPARα, which mediates its effects partly via the PPARα pathway.…”

Astrocyte Elevated Gene-1 (AEG-1) Regulates Lipid Homeostasis

“…In enterocytes, activation of LXR inhibits cholesterol absorption by down-regulating cholesterol transporter Npc1l1 and up-regulating cholesterol efflux proteins, Abca1, Abcg5, and Abcg8 (15). Activation of PPAR␣ in the enterocytes promotes ␤-oxidation of absorbed fatty acids, thereby downregulating fatty acid absorption into the circulation (23,24). Products of cholesterol metabolism, such as oxysterols, function as ligands for LXR, whereas fatty acids and fatty acid derivatives are endogenous ligands for PPAR␣ (17,36).…”

“…The majority of fatty acids are re-esterified into TG and excreted into chylomicrons. In the enterocytes, PPAR␣ promotes ␤-oxidation of fatty acids, thereby decreasing fatty acid absorption in the circulation (23,24).…”