Oral Supplementation of Phosphatidylcholine Attenuates the Onset of a Diet-Induced Metabolic Dysfunction–Associated Steatohepatitis in Female C57BL/6J Mice

Abstract

Background & AimsChanges in phosphatidylcholine levels in liver have been associated with the development of metabolic dysfunction-associated steatotic liver disease (MASLD). Here, the effects of supplementing phosphatidylcholine on the development of early signs of metabolic dysfunction-associated steatohepatitis (MASH) were assessed. MethodsMale and female C57BL/6J mice were fed a liquid control or a fructose-, fat- and/or cholesterol-rich diet (FrFC) for 7 or 8 weeks. The diets of female mice were fortified +/- phosphatidylcholine (12.5 mg/g diet). In liver tissue and portal blood, indices of liver damage, inflammation, and bacterial endotoxemia were measured. J774A.1 cells and human monocytes pre-incubated with phosphatidylcholine (0.38 mM) were challenged with lipopolysaccharide (LPS, 50-100 ng/ml) +/- the peroxisome proliferator-activated receptor gamma (PPARγ) activator pioglitazone (10 μM) or +/- an liver receptor homolog 1 (LRH-1) antagonist 1-(3´-(1-(2-(4-Morpholinyl)ethyl)-1H-pyrazol-3-yl)-3-biphenylyl)ethanon (1-10 μM). ResultsIn FrFC-fed mice the development of fatty liver and beginning of inflammation was associated with significantly lower hepatic phosphatidylcholine levels when compared to controls. Supplementing phosphatidylcholine significantly attenuated the development of fatty liver and inflammation, being associated with a protection against the induction of PPARγ2, and activation of nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha (IκBα) while Lrh1 expression was unchanged. The protective effects of phosphatidylcholine on the LPS-induced activation of J774A.1 cells and human monocytes were significantly attenuated by the PPARγ activator pioglitazone and the LRH-1 antagonist. ConclusionsOur data suggest that phosphatidylcholine levels in liver are lower in early MASH in mice and that a supplementation of phosphatidylcholine can diminish the development of MASLD through mechanisms involving LRH-1/PPARγ2/NFκB signaling.