Hardwick James P
Biochemistry and Molecular Pathology, Department of Integrative Medical Sciences, Northeastern Ohio Universities College of Medicine and Pharmacy (NEOUCOM/NEOUCOP), 4209 State Route 44, Rootstown, OH 44272, USA.
Biochem Pharmacol. 2008 Jun 15;75(12):2263-75. doi: 10.1016/j.bcp.2008.03.004. Epub 2008 Mar 15.
The cytochrome P450 gene 4 family (CYP4) consists of a group of over 63 members that omega-hydroxylate the terminal carbon of fatty acids. In mammals, six subfamilies have been identified and three of these subfamily members show a preference in the metabolism of short (C7-C10)-CYP4B, medium (C10-C16)-CYP4A, and long (C16-C26)-CYP4F, saturated, unsaturated and branched chain fatty acids. These omega-hydroxylated fatty acids are converted to dicarboxylic acids, which are preferentially metabolized by the peroxisome beta-oxidation system to shorter chain fatty acids that are transported to the mitochondria for complete oxidation or used either to supply energy for peripheral tissues during starvation or in lipid synthesis. The differential regulation of the CYP4A and CYP4F genes during fasting, by peroxisome proliferators and in non-alcoholic fatty liver disease (NAFLD) suggests different roles in lipid metabolism. The omega-hydroxylation and inactivation of pro-inflammatory eicosanoids by members of the CYP4F subfamily and the association of the CYP4F2 and CYP4F3 genes with inflammatory celiac disease indicate an important role in the resolution of inflammation. Several human diseases have been genetically linked to the expression CYP4 gene polymorphic variants, which may link human susceptibility to diseases of lipid metabolism and the activation and resolution phases of inflammation. Understanding how the CYP4 genes are regulated during the fasting and feeding cycles and by endogenous lipids will provide therapeutic avenues in the treatment of metabolic disorders of lipid metabolism and inflammation.
细胞色素P450基因4家族（CYP4）由一组超过63个成员组成，这些成员可对脂肪酸的末端碳进行ω-羟基化。在哺乳动物中，已鉴定出六个亚家族，其中三个亚家族成员在短链（C7-C10）脂肪酸（CYP4B）、中链（C10-C16）脂肪酸（CYP4A）和长链（C16-C26）脂肪酸（CYP4F）、饱和脂肪酸、不饱和脂肪酸和支链脂肪酸的代谢中表现出偏好。这些ω-羟基化脂肪酸会转化为二羧酸，二羧酸优先通过过氧化物酶体β-氧化系统代谢为较短链脂肪酸，这些较短链脂肪酸被转运至线粒体进行完全氧化，或用于在饥饿期间为外周组织提供能量，或用于脂质合成。在禁食期间、过氧化物酶体增殖剂作用下以及非酒精性脂肪性肝病（NAFLD）中，CYP4A和CYP4F基因的差异调节表明它们在脂质代谢中具有不同作用。CYP4F亚家族成员对促炎性类花生酸的ω-羟基化和失活作用，以及CYP4F2和CYP4F3基因与炎症性乳糜泻的关联，表明其在炎症消退中具有重要作用。几种人类疾病在基因上与CYP4基因多态性变体的表达相关联，这可能将人类对脂质代谢疾病的易感性与炎症的激活和消退阶段联系起来。了解CYP4基因在禁食和进食周期以及内源性脂质作用下是如何被调节的，将为治疗脂质代谢和炎症的代谢紊乱提供治疗途径。
