Microsomal triglyceride transfer protein restricts steroid production in Leydig cells by regulating SREBP2

Testicular Leydig cells produce testosterone. Decreases in serum testosterone reduce bone density, muscle mass, and sexual functions, and increase obesity and cardiovascular disease. Microsomal triglyceride transfer protein (MTP) is critical for lipoprotein secretion by the liver and intestine. MTP is expressed in the Leydig cells of human and mouse testes, but its function is unknown. MTP inhibition, knockdown, and gene ablation in mouse Leydig cells significantly increased steroid secretion after stimulation with cyclic AMP. MTP deficiency enhanced the expression of cholesterol metabolism genes, luteinizing hormone receptor, and steroid biosynthesis genes. Furthermore, MTP deficiency enhanced the expression and activity of SREBP2. ATAC sequencing revealed enhanced binding of SREBP2 to the promoters of genes in cholesterol metabolism and steroid biosynthesis pathways. SREBP2 knockdown in MTP-deficient cells significantly attenuated the cholesterol and progesterone biosynthesis pathways. These studies show that MTP regulates cholesterol and sex hormone production by modulating SREBP2 activity.