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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE333221 | GEO | 2026/07/27

REPOSITORIES: GEO

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Project description:There is increased interest in the potential protective role of dietary Ca in the development of metabolic disorders related to the metabolic syndrome. Ca-induced intestinal precipitation of fatty acids and bile acids as well as systemic metabolic effects of Ca on adipose tissue is proposed to play a causal role. In this experiment, we have studied all these aspects to validate the suggested protective effect of Ca supplementation, independent of other dietary changes, on the development of diet-induced obesity and insulin resistance. In our diet intervention study, C57BL/6J mice were fed high-fat diets differing in Ca concentrations (50 v. 150 mmol/kg). Faecal excretion analyses showed an elevated precipitation of intestinal fatty acids (2·3-fold; P < 0·01) and bile acids (2-fold; P < 0·01) on the high-Ca diet. However, this only led to a slight reduction in fat absorption (from 98 to 95 %; P < 0·01), mainly in the distal small intestine as indicated by gene expression changes. We found no effect on body-weight gain. Lipolysis and lipogenesis-related parameters in adipose tissue also showed no significant changes on the high-Ca diet, indicating no systemic effects of dietary Ca on adiposity. Furthermore, early gene expression changes of intestinal signaling molecules predicted no protective effect of dietary Ca on the development of insulin resistance, which was confirmed by equal values for insulin sensitivity on both diets. Taken together, our data do not support the proposed protective effect of dietary Ca on the development of obesity and/or insulin resistance, despite a significant increase in fecal excretion of fatty acids and bile acids. Keywords: Diet intervention study Nine-week-old mice were fed a high fat purified diet with a low calcium concentration of 50mmol/kg (LCa diet) or a high calcium concentration of 150mmol/kg (HCa diet) for 8 weeks. Body weight was recorded weekly and after 7 weeks of diet intervention an oral glucose tolerance test was performed. For microarray analysis, after 2 weeks of diet intervention, 6 mice per diet group were anaesthetized with a mixture of isofluorane (1.5%), nitrous oxide (70%) and oxygen (30%) and the small intestines were excised. Adhering fat and pancreatic tissue were carefully removed. The small intestines were divided in three equal parts along the proximal to distal axis (SI 1, SI 2 and SI 3) and microarray analysis was performed on pooled mucosal scrapings.

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

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