A 52-year-old woman with type 2 diabetes and obesity has steatohepatitis on liver biopsy. Her fasting insulin is markedly elevated. The most significant biochemical consequence of chronic hyperinsulinemia on hepatic lipid metabolism is:

• A Upregulation of hormone-sensitive lipase in adipose tissue
• B Increased hepatic fatty acid oxidation via CPT-I upregulation
• C Enhanced VLDL clearance by peripheral lipoprotein lipase
• D Stimulation of de novo lipogenesis via activation of SREBP-1c and ChREBP ✓

Explanation

Chronic hyperinsulinemia activates the transcription factor SREBP-1c, which upregulates all enzymes of de novo lipogenesis including ACC, fatty acid synthase, and stearoyl-CoA desaturase-1. ChREBP (carbohydrate response element binding protein) is co-activated by glucose-derived metabolites. Together, excess lipid synthesis overwhelms VLDL secretory capacity and beta-oxidation, causing triglyceride accumulation in hepatocytes as seen in non-alcoholic steatohepatitis.

Reference: Harper's Illustrated Biochemistry, 32nd ed.

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Written and medically reviewed by the StethoPrep medical team.