Peroxisomal β-oxidation stimulates cholesterol biosynthesis in the liver in diabetic mice

• Published in: The Journal of biological chemistry 2022-02, Vol.298 (2), p.101572-101572, Article 101572
• Main Authors: Zhang, Xiao, Wang, Yaoqing, Yao, Haoya, Deng, Senwen, Gao, Ting, Shang, Lin, Chen, Xiaocui, Cui, Xiaojuan, Zeng, Jia
• Format: Article
• Language: English
• Subjects: Animals; biosynthesis; cholesterol; Cholesterol - biosynthesis; Cholesterol - metabolism; diabetes; Diabetes Mellitus, Experimental - metabolism; fatty acid oxidation; Fatty Acids - metabolism; Hypercholesterolemia - metabolism; Liver - metabolism; Mice; Microbodies - metabolism; Oxidation-Reduction; peroxisome; Peroxisomes - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1016/j.jbc.2022.101572

Although diabetes normally causes an elevation of cholesterol biosynthesis and induces hypercholesterolemia in animals and human, the mechanism linking diabetes to the dysregulation of cholesterol biosynthesis in the liver is not fully understood. As liver peroxisomal β-oxidation is induced in the diabetic state and peroxisomal oxidation of fatty acids generates free acetate, we hypothesized that peroxisomal β-oxidation might play a role in liver cholesterol biosynthesis in diabetes. Here, we used erucic acid, a specific substrate for peroxisomal β-oxidation, and 10,12-tricosadiynoic acid, a specific inhibitor for peroxisomal β-oxidation, to specifically induce and suppress peroxisomal β-oxidation. Our results suggested that induction of peroxisomal β-oxidation increased liver cholesterol biosynthesis in streptozotocin-induced diabetic mice. We found that excessive oxidation of fatty acids by peroxisomes generated considerable free acetate in the liver, which was used as a precursor for cholesterol biosynthesis. In addition, we show that specific inhibition of peroxisomal β-oxidation decreased cholesterol biosynthesis by reducing acetate formation in the liver in diabetic mice, demonstrating a crosstalk between peroxisomal β-oxidation and cholesterol biosynthesis. Based on these results, we propose that induction of peroxisomal β-oxidation serves as a mechanism for a fatty acid-induced upregulation in cholesterol biosynthesis and also plays a role in diabetes-induced hypercholesterolemia.