PR002095 (Project)

Description:Obesity and fatty liver diseases-metabolic dysfunction-associated steatotic liver disease (MASLD and MASH) affect over a third of the global population and are exacerbated in individuals with reduced functional aldehyde dehydrogenase 2 (ALDH2), observed in approximately 560 million people. Current treatment to prevent disease progression to cancer remains inadequate, requiring innovative approaches. We observe that Aldh2-/- and Aldh2-/-Sptbn1+/- mice develop phenotypes of human Metabolic Syndrome (MetS) and MASH with a striking accumulation of endogenous aldehydes such as 4-hydroxynonenal (4-HNE). While phospholipids are often modified by reactive aldehydes that accumulate in the absence of ALDH2, to understand the mechanisms for the differences in liver metabolism in ASKO mice, we analyzed liver metabolomics and lipidomics from mice models. Briefly, C57BL/6 mice (n=15) were from 3 groups (WT, Aldh2-/-(ko), Aldh2-/-Sptbn1+/-(double), n=5 per group) and fed normal chow diet for 10 months. For quality control, 6 QC samples were also included in the analysis (total 21 samples). We observed that livers of Aldh2-/-Sptbn1+/- mice had substantially higher levels of all investigated phospholipids, including ≥ 2-fold increase in 26% of phosphatidylethanolamine (PE) lipid types and ≥ 2-fold increase in 32% of phosphatidylserine (PS) lipid types, compared to livers of WT mice. Similarly, increased abundances of TGs and diacylglycerides (DGs) lipid types were also observed in the livers of Aldh2-/-Sptbn1+/- mice. These results demonstrated that Aldehydes altered lipid metabolism which may be implicated in the progression of liver MetS, MASLD/MASH in Aldh2-/-Sptbn1+/- mice.