Intestinal lipase inhibition uncouples diet-induced obesity from MASH by remodeling the hepatic lipidome

Dietary fatty acids exert distinct effects on hepatic metabolism. Intestinal lipase inhibition, used clinically for obesity, promotes weight loss by indiscriminately reducing dietary fat absorption, yet its impact on hepatic lipid metabolism in metabolic dysfunction-associated steatohepatitis (MASH) remains poorly defined. Here, we examined the metabolic consequences of lipase inhibition of fat absorption in MASH. To induce MASH, C57BL/6J mice were fed the high-fat Gubra-Amylin NASH (GAN) diet with or without the lipase inhibitor orlistat for 32 weeks. Orlistat protected against diet-induced obesity by promoting fat malabsorption but failed to prevent the progression of hepatomegaly, steatosis, and fibrosis across longitudinal ultrasound imaging, biochemical assessments, and endpoint histology. Despite limiting weight gain, orlistat unexpectedly exacerbated hepatic inflammation. Lipidomic analyses revealed that indiscriminate inhibition of fat absorption depleted the liver of essential polyunsaturated fatty acids while increasing saturated fatty acids. This shift was associated with increased hepatic lipogenesis and proinflammatory signaling, preventing protection from MASH. In summary, lipase inhibition of intestinal fat absorption uncouples obesity from liver disease progression by reshaping the hepatic lipidome. These findings underscore the importance of dietary fat and hepatic lipid composition as key drivers of MASH pathogenesis.