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Non-Alcoholic Fatty Liver Disease (NAFLD) is a spectrum of liver diseases that encompass steatosis, Non-Alcoholic Steatohepatitis (NASH) and fibrosis. It is a major public health problem due to its frequency and potential complications (cirrhosis, hepatocellular carcinoma). At present, the monitoring of patients with steatosis or NASH is not fully coded and current treatments are not very effective. Research into the genetics and epigenetics of NAFLD is booming. While genetics studies modifications into the nucleotide sequence of genes, epigenetics studies modifications in the function of a gene that cannot be explained by alterations to the gene sequence. PNPLA3, TM6SF2 and MBOAT7-TMC4 are the 3 main genes for which single nucleotide polymorphisms are associated with steatosis, NASH and hepatic fibrosis, independently of insulin resistance and metabolic syndrome. MicroRNAs (miR), small non-coding RNAs inhibit messenger RNAs and thus regulate gene expression. The expression of some miRs in the liver is modified in NAFLD: miR 122 is decreased and miR 34a is increased. Some miRs are also found in the circulation: for example, miR 122 is increased in the case of NAFLD. Finally, the methylation of target genes is modified in NAFLD resulting in changes in their expression. This is particularly the case for PPAR, a key gene for lipid metabolism. In future, it is likely that substantial genetic and epigenetic data can be obtained for each individual from a simple blood sample allowing personalized monitoring and treatment for NAFLD, as for other diseases. [ABSTRACT FROM AUTHOR]

The proteolytic cleavage of Fibronectin type III domain-containing 5 (FNDC5) generates soluble irisin. Initially described as being mainly produced in muscle during physical exercise, irisin mediates adipose tissue thermogenesis and also regulates carbohydrate and lipid metabolism. The aim of this study was to evaluate the hepatic expression of FNDC5 and its role in hepatocytes in Non-Alcoholic Fatty Liver (NAFL). Here we report that hepatic expression of FNDC5 increased with hepatic steatosis and liver injury without impacting the systemic level of irisin in mouse models of NAFLD (HFD and MCDD) and in obese patients. The increased Fndc5 expression in fatty liver resulted from its upregulation in hepatocytes and non-parenchymal cells in mice. The local production of Fndc5 in hepatocytes was influenced by genotoxic stress and p53-dependent pathways. The down-regulation of FNDC5 in human HepG2 cells and in primary mouse hepatocytes increased the expression of PEPCK , a key enzyme involved in gluconeogenesis associated with a decrease in the expression of master genes involved in the VLDL synthesis (CIDEB and APOB). These alterations in FNDC5 -silenced cells resulted to increased steatosis and insulin resistance in response to oleic acid and N -acetyl glucosamine, respectively. The downregulation of Fndc5 also sensitized primary hepatocytes to apoptosis in response to TNFα, which has been associated with decreased hepatoprotective autophagic flux. In conclusion, our human and experimental data strongly suggest that the hepatic expression of FNDC5 increased with hepatic steatosis and its upregulation in hepatocytes could dampen the development of NAFLD by negatively regulating steatogenesis and hepatocyte death. • Hepatic FNDC5 is upregulated in NAFLD without impacting systemic levels of irisin in mouse and human. • Hepatocytes and non-parenchymal cells contribute to increased FNDC5 expression in fatty livers. • Hepatic genotoxic stress and p53 pathway activation could be involved in local upregulation of FNDC5. • FNDC5 in hepatocytes limits steatosis and cytokine-mediated apoptosis. [ABSTRACT FROM AUTHOR]

Background & Aims Cluster of differentiation (CD)44 regulates adipose tissue inflammation in obesity and hepatic leukocyte recruitment in a lithogenic context. However, its role in hepatic inflammation in a mouse model of steatohepatitis and its relevance in humans have not yet been investigated. We aimed to evaluated the contribution of CD44 to non-alcoholic steatohepatitis (NASH) development and liver injury in mouse models and in patients at various stages of non-alcoholic fatty liver disease (NAFLD) progression. Methods The role of CD44 was evaluated in CD44 −/− mice and after injections of an αCD44 antibody in wild-type mice challenged with a methionine- and choline-deficient diet (MCDD). In obese patients, hepatic CD44 (n = 30 and 5 NASH patients with a second liver biopsy after bariatric surgery) and serum sCD44 (n = 64) were evaluated. Results Liver inflammation (including inflammatory foci number, macrophage and neutrophil infiltration and CCL2/CCR2 levels), liver injury and fibrosis strongly decreased in CD44 −/− mice compared to wild-type mice on MCDD. CD44 deficiency enhanced the M2 polarization and strongly decreased the activation of macrophages by lipopolysaccharide (LPS), hepatocyte damage-associated molecular patterns (DAMPs) and saturated fatty acids. Neutralization of CD44 in mice with steatohepatitis strongly decreased the macrophage infiltration and chemokine ligand (CCL)2 expression with a partial correction of liver inflammation and injury. In obese patients, hepatic CD44 was strongly upregulated in NASH patients ( p = 0.0008) and correlated with NAFLD activity score (NAS) ( p = 0.001), ballooning ( p = 0.003), alanine transaminase ( p = 0.005) and hepatic CCL2 ( p <0.001) and macrophage marker CD68 ( p <0.001) expression. Correction of NASH was associated with a strong decrease in liver CD44 + cells. Finally, the soluble form of CD44 increased with severe steatosis ( p = 0.0005) and NASH ( p = 0.007). Conclusion Human and experimental data suggest that CD44 is a marker and key player of hepatic inflammation and its targeting partially corrects NASH. Lay summary Human and experimental data suggest that CD44, a cellular protein mainly expressed in immune cells, is a marker and key player of non-alcoholic steatohepatitis (NASH). Indeed, CD44 enhances the non-alcoholic fatty liver (NAFL) (hepatic steatosis) to NASH progression by regulating hepatic macrophage polarization (pro-inflammatory phenotype) and infiltration (macrophage motility and the MCP1/CCL2/CCR2 system). Targeting CD44 partially corrects NASH, making it a potential therapeutic strategy. [ABSTRACT FROM AUTHOR]