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

BACKGROUND & AIMS: Changes in phosphatidylcholine levels in the liver have been associated with the development of metabolic dysfunction - associated steatotic liver disease. Here, the effects of supplementing phosphatidylcholine on the development of early signs of metabolic dysfunction - associated steatohepatitis were assessed. METHODS: Male and female C57BL/6J mice were fed a liquid control or a fructose-, fat-, and/or cholesterol -rich diet for 7 or 8 weeks. The diets of female mice were forti fi ed +/- phosphatidylcholine (12.5 mg/g diet). In liver tissue and portal blood, indices of liver damage, in fl ammation, and bacterial endotoxemia were measured. J774A.1 cells and human monocytes preincubated with phosphatidylcholine (0.38 mmol/L) were challenged with lipopolysaccharide (50 - 100 ng/mL) +/- the peroxisome proliferator-activated receptor y (PPAR y ) activator pioglitazone (10 m mol/L) or +/- a liver receptor homolog 1 (LRH1) antagonist 1-(3 0 -[1-(2-[4-morpholinyl]ethyl)-1H-pyrazol-3- yl]-3-biphenylyl)ethanon (1 - 10 m mol/L). RESULTS: In fructose-, fat-, and/or cholesterol -rich diet - fed mice the development of fatty liver and the beginning of inflammation were associated with significantly lower hepatic phosphatidylcholine levels when compared with controls. Supplementing phosphatidylcholine signi fi cantly attenuated the development of fatty liver and in fl ammation, being associated with protection against the induction of PPAR y 2, and activation of nuclear factor of k light polypeptide gene enhancer in B -cell inhibitor a whereas Lrh1 expression was unchanged. The protective effects of phosphatidylcholine on the lipopolysaccharide-induced activation of J774A.1 cells and human monocytes were attenuated signi fi cantly by the PPAR y activator pioglitazone and the LRH-1 antagonist. CONCLUSIONS: Our data suggest that phosphatidylcholine levels in the liver are lower in early metabolic dysfunction - associated steatohepatitis in mice and that supplementation of phosphatidylcholine can diminish the development of metabolic dysfunction - associated steatotic liver disease through mechanisms involving LRH-1/PPAR y 2/ nuclear factor k -light -chain enhancer of activated B -cell signaling. (Cell Mol Gastroenterol Hepatol 2024;17:785 - 800; https:// doi.org/10.1016/j.jcmgh.2024.01.009)