Abstract
Progression of non-alcoholic fatty liver disease (NAFLD) from steatosis to non-alcoholic steatohepatitis (NASH) is a key step of NASH pathogenesis. The AP-1 transcription factor c-Jun is an important regulator of hepatic stress responses, but its contribution to NASH pathogenesis remains poorly defined. We therefore addressed c-Jun expression in liver biopsies of patients with steatosis and NASH. The role of c-Jun during NASH pathogenesis was analyzed mechanistically in c-Jun mutant mice fed with a methionine- and choline-deficient diet (MCDD). Disease progression from steatosis to NASH in patients correlated with increased c-Jun expression in hepatocytes, while its expression in non-parenchymal liver cells (NPLCs) particularly correlated with fibrosis. Analysis of untreated and MCDD-fed mice lacking c-Jun in hepatocytes (c-Jun∆li) revealed that c-Jun promotes hepatocyte survival, thereby protecting against the regenerative ductular reaction (DR) of Sox9/Osteopontin (Opn) co-expressing NPLCs, expression of the Opn receptor CD44 and fibrosis, which were all exacerbated in c-Jun∆li mice. Since Opn and c-Jun were co-expressed by NPLCs in mice and patients with NASH, we wondered whether the increased fibrosis observed in c-Jun∆li mice could be rescued by additional c-Jun deletion in NPLCs (c-Jun∆li*). c-Jun∆li* mice with NASH indeed exhibited reduced expression of Opn and CD44 in NPLCs, impaired DR and reduced fibrosis. A similar phenotype was observed in Opn knockout mice, suggesting that the observed functions of c-Jun were indeed Opn-dependent. In conclusion, c-Jun expression correlates with disease progression from steatosis to NASH in patients and exerts cell-type-specific functions in mice: In hepatocytes, it promotes cell survival thereby limiting the DR and fibrogenesis. In NPLCs, it rather promotes the DR and fibrogenesis by regulating expression of Opn and CD44.
Highlights
Non-alcoholic fatty liver disease (NAFLD) affects ~25% of the population in western countries
While c-Jun expression was absent in healthy livers as previously shown [10], patients with non-alcoholic fatty liver (NAFL) exhibited moderate nuclear c-Jun expression in hepatocytes and non-parenchymal liver cells (NPLCs), which was substantially increased in patients with nonalcoholic steatohepatitis (NASH) (Fig. 1a, b)
methionine- and choline-deficient diet (MCDD) feeding of c-Junf/f control mice resulted in strongly induced nuclear c-Jun expression in both, hepatocytes as well as NPLCs (Fig. 2a). c-Jun expression was absent in hepatocytes of c-JunΔli mice as determined by immunohistochemistry and immunoblotting of total liver lysates, confirming a high recombination efficiency (Fig. 2a, Supplementary Fig. 1C). mRNA expression of c-Fos, Fra-1 and Fra-2, which have been reported to form heterodimers with c-Jun during NASH [12], was not affected in c-JunΔli as compared with c-Junf/f livers (Supplementary Fig. 2A)
Summary
Non-alcoholic fatty liver disease (NAFLD) affects ~25% of the population in western countries. One quarter of patients with non-alcoholic fatty liver (NAFL) develops nonalcoholic steatohepatitis (NASH), which may further progress to liver cirrhosis and hepatocellular carcinoma (HCC) [1]. The prognosis of NASH closely correlates with the degree of liver fibrosis [2].
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