Phenotypic screen in vivo identifies sclerostin as a regulator for the development of nonalcoholic steatohepatitis in mice

Employing the piggyBac (PB) transposon insertion as a tool, we established a collection of >5000 mouse strains for phenotypic screen in vivo. A pipeline was established in order to identify mutations which contribute to the development of lipid metabolism disorder and liver diseases with the serum level of triglyceride (TG) as readout. Among 9 mouse strains, one strain of mouse was selected with elevated TG, which contained with an insertion to the 3’ UTR of Sost gene (SostPB/- mice) and this insertion induced the overexpression of Sost mRNA and SOST protein in multiple tissues. When fed on a MCD diet, SostPB/- mice showed higher level of lipid content, fibrosis and inflammationin the liver, which indicated that the WNT signaling inhibitor SOST aggravates the liver damages in the mice with NASH. To investigate the related mechanism, RNA-seq and targeted metabolomics were employed. SostPB/- mice showed upregulation of oxygen radical-related genes and decrease of vitamin C. Dietary supplement of vitamin C via drinking water normalized the changes of liver lipid content, fibrosis and inflammationin of SostPB/- mice.These results indicated the vitamin C is the key metabolite mediating the effects of SOST on the development of NASH.