Abstract：
Fatty acid omega hydroxylase P450s consist of enzymes that hydroxylate various chain-length saturated and unsaturated fatty acids (FAs) and bioactive eicosanoid lipids. The human cytochrome P450 gene 4 family (CYP4) consists of 12 members that are associated with several human diseases. However, their role in the progression of metabolic dysfunction-associated fatty liver disease (MASLD) remains largely unknown. It has long been thought that the induction of CYP4 family P450 during fasting and starvation prevents FA-related lipotoxicity through FA metabolism to dicarboxylic acids that are chain-shortened in peroxisomes and then transported to the mitochondria for complete oxidation. Several studies have revealed that peroxisome succinate transported to the mitochondria is used for gluconeogenesis during fasting and starvation, and recent evidence suggests that peroxisome acetate can be utilized for lipogenesis and lipid droplet formation as well as epigenetic modification of gene transcription. In addition, omega hydroxylation of the bioactive eicosanoid arachidonic acid to 20-Hydroxyeicosatetraenoic acid (20-HETE) is essential for activating the GPR75 receptor, leading to vasoconstriction and cell proliferation. Several mouse models of diet-induced MASLD have revealed the induction of selective CYP4A members and the suppression of CYP4F during steatosis and steatohepatitis, suggesting a critical metabolic role in the progression of fatty liver disease. Thus, to further investigate the functional roles of CYP4 genes, we analyzed the differential gene expression of 12 members of CYP4 gene family in datasets from the Gene Expression Omnibus (GEO) from patients with steatosis, steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. We also observed the differential expression of various CYP4 genes in the progression of MASLD, indicating that different CYP4 members may have unique functional roles in the metabolism of specific FAs and eicosanoids at various stages of fatty liver disease. These results suggest that targeting selective members of the CYP4A family is a viable therapeutic approach for treating and managing MASLD.
摘要：
脂肪酸ω羟化酶P450由羟基化各种链长的饱和和不饱和脂肪酸(FA)和生物活性类二十烷类脂质的酶组成。人细胞色素P450基因4家族(CYP4)由与几种人类疾病相关的12个成员组成。然而,它们在代谢功能障碍相关脂肪性肝病(MASLD)进展中的作用目前尚不清楚.长期以来，人们一直认为在禁食和饥饿期间CYP4家族P450的诱导通过FA代谢为二羧酸来防止FA相关的脂毒性，这些二羧酸在过氧化物酶体中被链缩短，然后被转运到线粒体进行完全氧化。一些研究表明，在禁食和饥饿期间，转运到线粒体的过氧化物酶体琥珀酸用于糖异生，最近的证据表明，过氧化物酶体乙酸盐可用于脂肪生成和脂滴形成以及基因转录的表观遗传修饰。此外,生物活性二十碳素花生四烯酸的omega羟基化为20-羟基二十碳四烯酸（20-HETE）对于激活GPR75受体至关重要，导致血管收缩和细胞增殖。几种饮食诱导的MASLD小鼠模型揭示了在脂肪变性和脂肪性肝炎期间选择性CYP4A成员的诱导和CYP4F的抑制,提示在脂肪肝疾病进展中的关键代谢作用。因此，为了进一步研究CYP4基因的功能作用，我们分析了来自脂肪变性患者的基因表达综合（GEO）的数据集中CYP4基因家族的12个成员的差异基因表达，脂肪性肝炎,纤维化，肝硬化,和肝细胞癌。我们还观察到各种CYP4基因在MASLD进展中的差异表达,表明不同的CYP4成员可能在脂肪肝疾病的各个阶段在特定FAs和类二十烷酸的代谢中具有独特的功能作用。这些结果表明靶向CYP4A家族的选择性成员是治疗和管理MASLD的可行治疗方法。
