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

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 beta-oxidation is induced in the diabetic state and peroxisomal oxidation of fatty acids generates free acetate, we hypothesized that peroxisomal beta-oxidation might play a role in liver cholesterol biosynthesis in diabetes. Here, we used erucic acid, a specific substrate for peroxisomal beta-oxidation, and 10,12-tricosadiynoic acid, a specific inhibitor for peroxisomal beta-oxidation, to specifically induce and suppress peroxisomal beta-oxidation. Our results suggested that induction of peroxisomal beta-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 beta-oxidation decreased cholesterol biosynthesis by reducing acetate formation in the liver in diabetic mice, demonstrating a crosstalk between peroxisomal beta-oxidation and cholesterol biosynthesis. Based on these results, we propose that induction of peroxisomal beta-oxidation serves as a mechanism for a fatty acidinduced upregulation in cholesterol biosynthesis and also plays a role in diabetes-induced hypercholesterolemia.

Automated summary

This study reveals the mechanism linking diabetes to the dysregulation of cholesterol biosynthesis in the liver. It shows that peroxisomal beta-oxidation plays a significant role in liver cholesterol biosynthesis by generating free acetate as a precursor. It suggests that induction of peroxisomal beta-oxidation serves as a mechanism for upregulation in cholesterol biosynthesis and contributes to diabetes-induced hypercholesterolemia.