Liraglutide exerts protective effects on MASLD independently of lipophagy, and the combination with kombucha presents no additional advantage

Abstract Metabolic dysfunction – associated steatotic liver disease (MASLD) has a high global prevalence, requiring effective therapeutic options. This study investigated the effects of liraglutide and kombucha, alone and in combination, in a murine model of high-fat diet (HFD)-induced MASLD. Metabolic parameters, body composition, liver histology, lipid profile, and markers of lipophagy were evaluated. The results demonstrate that liraglutide reduced body weight, fat mass, and lean mass, as well as food and caloric intake, fasting blood glucose, hepatic triglycerides (TG), steatosis, and fibrosis, improved the lipid profile and glucose tolerance, and increased lysosomal acid lipase (LAL) expression in the liver. Kombucha reduced lean mass, liver steatosis, hepatic TG, food and caloric intake, fasting blood glucose, low-density lipoprotein cholesterol (LDL-C), and liver fibrosis, in addition to improving glucose tolerance. However, the combination of treatments did not show synergistic effects superior to those of liraglutide alone. Although liraglutide independently impacted LAL expression, none of the other lipophagy markers were modulated in the liver, suggesting that the beneficial mechanisms of action are independent of the lipophagy pathway. It is concluded that both liraglutide and kombucha are valid strategies for mitigating MASLD, but the combination does not offer superior advantages over liraglutide monotherapy. Competing Interest Statement The authors have declared no competing interest. Footnotes jeniferalmeida{at}icb.usp.br (J.S.A.); andreoti{at}icb.usp.br (S.A.); tatiana.obara{at}usp.br (T.Y.O.); biancalugatti{at}usp.br (B.L.C.F.); rodrigogentile{at}usp.br (R.S.O.G.); Abbreviations - MASLD - Metabolic dysfunction–associated steatotic liver disease - LDL-C - Low-density lipoprotein cholesterol - HFD - High-fat diet - MASH - Metabolic dysfunction–associated steatohepatitis - LAL - Lysosomal acid lipase - GLP-1 - Glucagon-like peptide-1 - FDA - Food and Drug Administration - T2DM - Type 2 diabetes mellitus - AUC - Area under the curve - log10 - Base-10 logarithm - oGTT - Oral glucose tolerance test - TG - Triglycerides - TC - Total cholesterol - HDL-C - High-density lipoprotein cholesterol - VLDL-C - Very low-density lipoprotein cholesterol - ORO - Oil Red O - H&E - Hematoxylin and Eosin - PSR - Picrosirius Red - ALT - Alanine aminotransferase - AST - Aspartate aminotransferase - LC3-II - Microtubule-Associated Protein 1A/1B-Light Chain 3 - p62 - Sequestosome-1 - Atg7 - Autophagy Related 7