| First Author | Darlyuk-Saadon I | Year | 2021 |
| Journal | Proc Natl Acad Sci U S A | Volume | 118 |
| Issue | 14 | PubMed ID | 33811139 |
| Mgi Jnum | J:319619 | Mgi Id | MGI:6693400 |
| Doi | 10.1073/pnas.2018069118 | Citation | Darlyuk-Saadon I, et al. (2021) Active p38alpha causes macrovesicular fatty liver in mice. Proc Natl Acad Sci U S A 118(14):e2018069118 |
| abstractText | One third of the western population suffers from nonalcoholic fatty liver disease (NAFLD), which may ultimately develop into hepatocellular carcinoma (HCC). The molecular event(s) that triggers the disease are not clear. Current understanding, known as the multiple hits model, suggests that NAFLD is a result of diverse events at several tissues (e.g., liver, adipose tissues, and intestine) combined with changes in metabolism and microbiome. In contrast to this prevailing concept, we report that fatty liver could be triggered by a single mutated protein expressed only in the liver. We established a transgenic system that allows temporally controlled activation of the MAP kinase p38alpha in a tissue-specific manner by induced expression of intrinsically active p38alpha allele. Here we checked the effect of exclusive activation in the liver. Unexpectedly, induction of p38alpha alone was sufficient to cause macrovesicular fatty liver. Animals did not become overweight, showing that fatty liver can be imposed solely by a genetic modification in liver per se and can be separated from obesity. Active p38alpha-induced fatty liver is associated with up-regulation of MUC13, CIDEA, PPARgamma, ATF3, and c-jun mRNAs, which are up-regulated in human HCC. Shutting off expression of the p38alpha mutant resulted in reversal of symptoms. The findings suggest that p38alpha plays a direct causative role in fatty liver diseases and perhaps in other chronic inflammatory diseases. As p38alpha activity was induced by point mutations, it could be considered a proto-inflammatory gene (proto-inflammagene). |
