Reduced cholesterol absorption upon PPARδ activation coincides with decreased intestinal expression of NPC1L1

Abstract

Peroxisome proliferator-activated receptors (PPARs) control the transcription of genes involved in lipid metabolism. Activation of PPARδ may have antiatherogenic effects through the increase of plasma HDL, theoretically promoting reverse cholesterol transport from peripheral tissues toward the liver for removal via bile and feces. Effects of PPARδ activation by GW610742 were evaluated in wild-type and Abca1-deficient (Abca1−/−) mice that lack HDL. Treatment with GW610742 resulted in an ∼50% increase of plasma HDL-cholesterol in wild-type mice, whereas plasma cholesterol levels remained extremely low in Abca1−/− mice. Yet, biliary cholesterol secretion rates were similar in untreated wild-type and Abca1−/− mice and unaltered upon treatment. Unexpectedly, PPARδ activation led to enhanced fecal neutral sterol loss in both groups without any changes in intestinal Abca1, Abcg5, Abcg8, and 3-hydroxy-3-methylglutaryl-coenzyme A reductase expression. Moreover, GW610742 treatment resulted in a 43% reduction of fractional cholesterol absorption in wild-type mice, coinciding with a significantly reduced expression of the cholesterol absorption protein Niemann-Pick C1-like 1 (Npc1l1) in the intestine. PPARδ activation is associated with increased plasma HDL and reduced intestinal cholesterol absorption efficiency that may be related to decreased intestinal Npc1l1 expression.Thus, PPARδ is a promising target for drugs aimed to treat or prevent atherosclerosis.

Keywords

• Niemann-Pick C1-like 1
• peroxisome proliferator-activated receptor δ
• nuclear receptors
• high density lipoprotein-cholesterol