TLR4 Modulates Simvastatin’s Impact on HDL Cholesterol and Glycemic Control

Statins lower cardiovascular risk by inhibiting HMG-CoA reductase, with their efficacy and adverse effects linked to SREBP-regulated cholesterol metabolism. Nutritional states— particularly the alternating fasting and feeding cycles, rather than intrinsic circadian rhythms— exert tight control over hepatic lipid metabolism via SREBP-mediated regulation of cholesterol and fatty acid synthesis. We exploited the natural diurnal oscillations in food intake in mice to determine how nutritional state modulates simvastatin’s metabolic actions. When administered during fasting, simvastatin impaired glucose homeostasis through SREBP-2–driven autophagy that enhanced PPARα activity, whereas simvastatin given during feeding reduced HDL cholesterol and improved glucose metabolism. Mechanistically, a feeding-induced surge in lipopolysaccharide (LPS) suppressed hepatic oxysterol synthesis, thereby enabling simvastatin to further deplete oxysterols and inhibit activation of LXR and SREBP-1c—key regulators of PPARα signaling under both postprandial and fasting conditions. This cascade resulted in decreased HDL cholesterol levels and improved glycemic control. Moreover, TLR4 deficiency disrupted the LPS–simvastatin interplay on LXR/SREBP-1c/PPARα signaling, reversing the HDL-lowering and glucose-improving effects seen during feeding. Together, these results identify feeding-induced LPS–TLR4 signaling as a critical determinant of simvastatin’s metabolic effects and suggest strategies to optimize statin therapy based on nutritional state.