Kroetz D L, Yook P, Costet P, Bianchi P, Pineau T
Department of Biopharmaceutical Sciences, School of Pharmacy, University of California, San Francisco, California 94143, USA.
J Biol Chem. 1998 Nov 20;273(47):31581-9. doi: 10.1074/jbc.273.47.31581.
The hepatic CYP4A enzymes are important fatty acid and prostaglandin omega-hydroxylases that are highly inducible by fibric acid hypolipidemic agents and other peroxisome proliferators. Induction of the CYP4A enzymes by peroxisome proliferators is mediated through the nuclear peroxisome proliferator-activated receptor alpha (PPARalpha). Fatty acids have recently been identified as endogenous ligands of PPARalpha, and this receptor has been implicated in the regulation of lipid homeostasis. In the present report we characterized the induction of the hepatic CYP4A genes in rats during the altered lipid metabolism associated with starvation and diabetes. The mRNA levels of CYP4A1, CYP4A2, and CYP4A3 were induced 7-17-fold in the livers of fasted animals and 3-8-fold in the livers of diabetic animals. This was accompanied by corresponding changes in CYP4A protein levels and arachidonic and lauric acid omega-hydroxylase activity. Interestingly, feeding animals after the fasting period caused as much as an 80% suppression of CYP4A mRNA levels, whereas CYP4A protein levels and functional activity returned to control values. A second PPARalpha-responsive gene, acyl-CoA oxidase, was also induced in rat liver by diabetes and fasting. By using PPARalpha-deficient mice, we unambiguously demonstrated that PPARalpha is strictly required for hepatic CYP4A induction by starvation and diabetes. Similarly, induction of hepatic thiolase and bifunctional enzyme also required expression of PPARalpha. This represents the first evidence for the pathophysiologically induced activation of a nuclear receptor.
肝脏CYP4A酶是重要的脂肪酸和前列腺素ω-羟化酶，可被纤维酸类降血脂药物和其他过氧化物酶体增殖剂高度诱导。过氧化物酶体增殖剂对CYP4A酶的诱导是通过核过氧化物酶体增殖物激活受体α（PPARα）介导的。脂肪酸最近被确定为PPARα的内源性配体，并且该受体与脂质稳态的调节有关。在本报告中，我们描述了在与饥饿和糖尿病相关的脂质代谢改变期间大鼠肝脏CYP4A基因的诱导情况。CYP4A1、CYP4A2和CYP4A3的mRNA水平在禁食动物的肝脏中诱导增加7至17倍，在糖尿病动物的肝脏中诱导增加3至8倍。这伴随着CYP4A蛋白水平以及花生四烯酸和月桂酸ω-羟化酶活性的相应变化。有趣的是，禁食期后给动物喂食会导致CYP4A mRNA水平抑制高达80%，而CYP4A蛋白水平和功能活性恢复到对照值。另一个PPARα反应性基因酰基辅酶A氧化酶也在大鼠肝脏中被糖尿病和禁食诱导。通过使用PPARα缺陷小鼠，我们明确证明PPARα是饥饿和糖尿病诱导肝脏CYP4A所严格必需的。同样，肝脏硫解酶和双功能酶的诱导也需要PPARα的表达。这代表了核受体在病理生理条件下诱导激活的首个证据。
