Liver X receptor-α (LXRα) regulates cellular cholesterol abundance and potently activates hepatic lipogenesis. Here we show that at least 1 in 450 people in the UK Biobank carry functionally impaired mutations in LXRα, which is associated with biochemical evidence of hepatic dysfunction. On a western diet, male and female mice homozygous for a dominant negative mutation in LXRα have elevated liver cholesterol, diffuse cholesterol crystal accumulation and develop severe hepatitis and fibrosis, despite reduced liver triglyceride and no steatosis. This phenotype does not occur on low-cholesterol diets and can be prevented by hepatocyte-specific overexpression of LXRα. LXRα knockout mice exhibit a milder phenotype with regional variation in cholesterol crystal deposition and inflammation inversely correlating with steatosis. In summary, LXRα is necessary for the maintenance of hepatocyte health, likely due to regulation of cellular cholesterol content. The inverse association between steatosis and both inflammation and cholesterol crystallization may represent a protective action of hepatic lipogenesis in the context of excess hepatic cholesterol.

肝脏 X 受体-α （LXRα） 调节细胞胆固醇丰度并有效激活肝脏脂肪生成。在这里，我们表明，英国生物样本库中至少有 1/450 的人携带 LXRα 功能受损突变，这与肝功能障碍的生化证据有关。在西方饮食中，尽管肝脏甘油三酯降低且无脂肪变性，但 LXRα 显性阴性突变纯合子的雄性和雌性小鼠肝脏胆固醇升高，弥漫性胆固醇晶体积累并发展为严重的肝炎和纤维化。这种表型不会发生在低胆固醇饮食中，可以通过肝细胞特异性过表达 LXRα 来预防。LXRα 敲除小鼠表现出较温和的表型，胆固醇晶体沉积和炎症的区域差异与脂肪变性呈负相关。总之，LXRα 对于维持肝细胞健康是必需的，这可能是由于调节细胞胆固醇含量。脂肪变性与炎症和胆固醇结晶之间的负相关可能代表在肝脏胆固醇过量的情况下肝脏脂肪生成的保护作用。