Active p38α causes macrovesicular fatty liver in mice

Abstract

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 p38α in a tissue-specific manner by induced expression of intrinsically active p38α allele. Here we checked the effect of exclusive activation in the liver. Unexpectedly, induction of p38α 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 p38α-induced fatty liver is associated with up-regulation of MUC13, CIDEA, PPARγ, ATF3, and c-jun mRNAs, which are up-regulated in human HCC. Shutting off expression of the p38α mutant resulted in reversal of symptoms. The findings suggest that p38α plays a direct causative role in fatty liver diseases and perhaps in other chronic inflammatory diseases. As p38α activity was induced by point mutations, it could be considered a proto-inflammatory gene (proto-inflammagene).

MAPK-Activated Protein Kinases: Servant or Partner?

“…an ARE-mRNA cis-regulatory binding protein form an intracellular, mutually stabilizing complex and that deletion of p38α or MK2 leads to a reduction of the partner protein due to its destabilization (reviewed in 8). Interestingly, long-term activation of the complex leads to its dissociation and instability of MK2 due to Mdm2-dependent ubiquitination and targeting of MK2 to the proteasome (11); in addition, a transgenic mouse overexpressing constitutively active p38α displays reduced levels of endogenous MK2 (157,158).…”

P38γ modulates the lipid metabolism in non‐alcoholic fatty liver disease by regulating the JAK–STAT signaling pathway

“…For example, P38α‐depleted macrophages were shown to alleviate fatty liver changes in hepatocytes 32 . Active P38α played a direct pathogenic role in fatty liver disease and played a key role in the etiology of hepatic inflammatory diseases 33 . Studies have shown that P38γ controls inflammation by regulating the production of TNF‐α in macrophages 34 .…”

“…32 Active P38α played a direct pathogenic role in fatty liver disease and played a key role in the etiology of hepatic inflammatory diseases. 33 Studies have shown that P38γ controls inflammation by regulating the production of TNF-α in macrophages. 34 In addition, a previous study demonstrated that mice were short of P38γ/δ in bone marrow cells can resist diet-guided fatty liver, accumulation of hepatic triglycerides, and glucose intolerance.…”

Differential Modulation of the Phosphoproteome by the MAP Kinases Isoforms p38α and p38β

“…It implies that the effects of constant MAPK activity are different to those of transient responses. The role of p38 in the etiology of these diseases is not clear, but as its activation per se in the liver is sufficient to impose some disease symptoms, it may play a causative role in fatty liver diseases [28] and other maladies [29][30][31][32][33]. Moreover, recent studies have shown that p38s play a role in the behavior and function of cancer stem cells [4].…”