Dividing paths in fatty liver disease

Nonalcoholic steatohepatitis (NASH) is associated with obesity and is a more severe and progressive form of nonalcoholic fatty liver disease (NAFLD), showing advanced fibrosis and hepatic inflammation. Simple steatosis is a less severe form of NAFDL and can progress into NASH. A subset of patients with NASH develop hepatocellular carcinoma (HCC) with advanced fibrosis and cirrhosis, while others do not. Also, an increasing number of patients with simple steatosis develop HCC but without symptoms of advanced fibrosis and cirrhosis, indicating that NASH might not be required for HCC development. Grohmann, Wiede et al. have now reported in Cell that the pathologies of NASH and HCC in obesity can be driven by two independent pathways.

Credit: Philip Patenall/Springer Nature Limited

Oxidation of protein tyrosine phosphatases (PTPs), which leads to their inactivation, occurs in livers of high-fat diet (HFD)-fed mice that develop NAFL but not NASH. Following up on their previous studies and looking into whether PTP oxidation is associated with NASH and/or HCC, the researchers used C57BL/6 mice fed with a normal chow diet (NCD), HFD (promoting obesity, insulin resistance and simple steatosis) or choline-deficient HFD (CD-HFD; promoting obesity, insulin resistance and progression of simple steatosis to NASH). Indeed, PTP oxidation status, including that of T cell PTP (TCPTP), was increased in HFD-fed mice and further increased in CD-HFD fed mice, compared with NCD mice.

The researchers chose to focus on TCPTP, because TCPTP oxidation was higher in livers of obese patients with NAFLD compared with livers of those without steatosis. TCPTP dephosphorylates and inactivates STAT1 and STAT3, and phosphorylation of STAT1 and STAT3 was increased in livers of HFD and CD-HFD mice compared with NCD mice as well as in livers of obese patients with NAFLD compared with non-obese patients without NAFLD. C57BL/6 mice with deletion of TCPTP in hepatocytes (Alb-Cre;Ptpn2^fl/fl) but not control mice (Ptpn2^fl/fl) developed NASH after being fed a HFD, which included NASH-associated increased immune cell infiltration and ectopic lymphoid-like structure formation, as well as increased liver damage. Immune cell infiltrates were composed of increased numbers of CD4⁺ and CD8⁺ T cells, and also contained increased numbers of immunoglobulin A (IgA)-positive cells, which express high levels of programmed cell death 1 ligand 1 (PD-L1) compared with Ptpn2^fl/fl mice. Importantly, one in three Alb-Cre;Ptpn2^fl/fl mice fed with HFD developed aggressive HCC, in contrast to HFD-fed Ptpn2^fl/fl mice, none of which developed HCC.

To analyse STAT1 and/or STAT3 function in NASH and HCC development, the researchers generated Alb-Cre;Ptpn2^fl/fl mice with heterozygous deficiency of STAT1 or STAT3, leading to correction of the increased phosphorylation of either protein in hepatocytes. Importantly, STAT1 heterozygosity (Stat1^fl/+) repressed hepatic inflammation, decreased immune cell recruitment and decreased fibrosis in HFD-fed Alb-Cre;Ptpn2^fl/fl mice, compared with control mice. By contrast, STAT3 heterozygosity (Stat3^fl/+) did not reduce immune cell recruitment or fibrosis in HFD-fed Alb-Cre;Ptpn2^fl/fl mice, compared with control mice. However, again in contrast to STAT1 heterozygosity, STAT3 heterozygosity completely repressed the development of HCC in HFD-fed Alb-Cre;Ptpn2^fl/fl mice, compared with control mice.

TCPTP oxidation was higher in livers of obese patients

NASH and HCC in obesity are driven by increased STAT1 and STAT3 signalling, respectively, as a result of increased TCPTP oxidation. Although requiring validation, this study calls into question the predominant view of NASH preceding HCC in obesity.