Hepatocyte-specific inactivation of the epigenetic regulator SUV420H1 improves MASLD in mice

Metabolic-dysfunction-Associated-Steatotic-Liver-Disease (MASLD) is the hepatic manifestation of the metabolic syndrome characterized by dyslipidemia, insulin resistance, liver inflammation and fibrosis. MASLD is influenced by nutritional, environmental, and genetic factors. The epigenetic regulators Suv420h1-h2 have been identified as inhibitors of Ppar signaling in brown adipose tissue. Recently, a GWAS performed on mice identified a common association between liver iron and triglyceride levels in a region of chromosome 7 containing, among others, Suv420h2. We have previously shown that mice with Suv420h1-Suv420h2 deletion are protected from MASLD. However, their specific role in disease progression is unknown. To investigate whether Suv420h1 can protect against MASLD, we generated mice lacking h1 only in hepatocytes (h1-LCKO) that were fed a fructose-palmitate-cholesterol-rich diet (FPC) for 16 weeks. FPC-h1-LCKO mice gain less weight compared to FPC-control mice. Glucose levels are lower and insulin sensitivity improves in the absence of h1. Hepatomegaly, liver triglyceride content and lipid droplets are reduced in h1-LCKO mice. Interestingly, the expression of genes associated with FPC-induced inflammation and fibrosis is comparable to that of FPC-control mice. However, fibrosis measured with Sirius Red is lower, and accordingly, the marker Bmp8b associated with disease severity is also greatly reduced in h1-LCKO mice. Of note, the expression of Ppar-alpha is increased in the liver of FPC-h1-LCKO mice, suggesting that it may be involved in disease amelioration. Overall, these data show that hepatocyte-specific deletion of Suv420h1 plays a protective role in diet-induced MASLD and complications. Further studies are ongoing to identify the pathways modulated by Suv420h1 in the liver.