出版社：American Society for Biochemistry and Molecular Biology
摘要：Peroxisome proliferator-activated receptors (PPARs) control the transcription of genes involved in lipid metabolism. Activation of PPAR 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 PPAR 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, PPAR 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. PPAR activation is associated with increased plasma HDL and reduced intestinal cholesterol absorption efficiency that may be related to decreased intestinal Npc1l1 expression.
Thus, PPAR is a promising target for drugs aimed to treat or prevent atherosclerosis.
Abbreviations: Abca1–/–, Abca1-deficient; FPLC, fast-protein liquid chromatography; Hmgr, 3-hydroxy-3-methylglutaryl-coenzyme A reductase; Mdr2, multidrug resistance P-glycoprotein 2; NPC1L1, Niemann-Pick C1-like 1; Pdk4, pyruvate dehydrogenase kinase isoenzyme 4; PPAR, peroxisome proliferator-activated receptor; RCT, reverse cholesterol transport; Sr-b1, scavenger receptor B1
关键词：Niemann-Pick C1-like 1 • peroxisome proliferator-activated receptor • nuclear receptors • high density lipoprotein-cholesterol
