Investigating the Mechanisms and Therapeutic Strategies for Hypercholesterolemia-Induced MASLD

Abstract: Metabolic dysfunction-associated steatotic liver disease (MASLD) presents a significant health challenge. Cholesterol metabolism is tightly linked to MASLD, including hepatic steatosis, fibrosis, and steatohepatitis. However, the precise mechanisms by which elevated cholesterol levels worsen MASLD remain unclear. This proposal seeks to unravel the impact of intracellular cholesterol distribution on MASLD. The Aster protein family, particularly Aster-C found exclusively in hepatocytes, is implicated in non-vesicular cholesterol transport from the plasma membrane to the endoplasmic reticulum (ER). Our preliminary data suggest that loss of Aster-C in hepatocytes reduces lipid accumulation and liver damage in MASLD. We hypothesize that elevated cholesterol levels disrupt its normal intracellular distribution, aggravating MASLD. We hypothesis that loss of Aster-C reduces ER cholesterol accumulation in response to dietary cholesterol, activating Nrf1/Nfe2L1, suppressing CD36 expression, and subsequently lowering fatty acid uptake. In Aim 1, we will elucidate the mechanisms by which loss of Aster-C protects hepatocytes from lipid accumulation. In Aim 2, we will test whether pharmacologically inhibiting Aster-C improves MASLD pathogenesis in high-cholesterol diet-fed mice. In summary, this research aims to uncover molecular-level insights into the role of hypercholesterolemia in MASLD and identify potential therapeutic targets and approaches for treatment.