Dual Role of FLVCR1a in Acute and Chronic Liver Disease

Liver diseases, which can be classified as acute or chronic, encompass a broad spectrum of conditions that impair liver function and cause tissue damage. Heme and choline are critical players in liver physiology and pathology. Heme, a key component of hemoproteins like electron transport chain complexes, P450 cytochromes, and catalase, is essential for regulating cellular energy metabolism. Choline, an important micronutrient, is involved in phospholipid synthesis and cholesterol metabolism, with one of its derivatives, phosphatidylcholine, maintaining cell membrane integrity and facilitating lipid transport and the formation of very low-density lipoproteins. Feline leukemia virus subgroup C receptor 1a (FLVCR1a) is a membrane transporter that imports choline and ethanolamine, acts as a positive regulator of heme synthesis, and contributes to energy production in cells. In mice, hepatocyte-specific deletion of FLVCR1a impairs cytochrome activity, and leads to iron accumulation and oxidative stress. Based on these findings, we hypothesized that FLVCR1a is involved in both acute and chronic liver injury. To explore this hypothesis, we used a hepatocyte-specific Flvcr1a knockout (LivKO) mouse model. Acute liver injury was induced via bile duct ligation (BDL), while chronic liver injury was modeled by feeding mice a high-fat, high-fructose (HFHF) diet to mimic Metabolic dysfunction-associated steatotic liver disease (MASLD). Both male and female mice were analyzed to account for the disease's sexually dimorphic nature. Under standard laboratory conditions, LivKO mice exhibited impaired glucose and lipid metabolism, increased fatty acid uptake, β-oxidation, TCA cycle enzyme activity, and elevated cholesterol levels, alongside reduced glucose uptake and glycolysis. Following BDL, LivKO mice showed reduced hepatic fibrosis, inflammation, and serum bilirubin levels 8 days post-surgery, although these improvements were not sustained during prolonged duct obstruction, which led to chronic disease. In the MASLD model, female LivKO mice gained more weight and accumulated more hepatic lipid droplets after 12 weeks on the HFHF diet compared to controls, while the diet effects were milder in males, possibly due to a sex-dependent delay in disease progression. Overall, these findings suggest that FLVCR1a regulates glucose and lipid metabolism in the liver and plays a role in the response to both acute and chronic liver injury.