Osr1-mediated mesothelial transition of liver mesenchymal cells exacerbates fibrotic liver damage.

In chronic liver diseases, hepatic stellate cells (HSCs) are induced to form the myofibroblasts responsible for scar formation, leading to liver fibrosis and cirrhosis. Here, single-cell RNA sequencing with in vivo lineage tracing in nonalcoholic steatohepatitis (NASH) model mice reveals a subpopulation of HSCs transitioning back to a state resembling their developmental precursors, mesothelial cells (MCs), after liver injury. These damage-associated intermediates between HSCs and MCs (DIHMs) can be traced with a dual recombinase system by labeling Krt19-expressing cells within prelabeled Pdgfrb+ HSCs, and DIHMs highly express inflammation- and fibrosis-associated genes. Cre and Dre-inducible depletion of DIHMs by administering diphtheria toxin reduces liver fibrosis and alleviates liver damage in NASH model mice. Importantly, knockdown of Osr1, a zinc finger transcription factor of the OSR gene family, can block DIHM induction in vitro. Conditional knockout Osr1 in Pdgfrb-expressing mesenchymal cells in NASH model mice can reduce liver fibrosis in vivo. Our study collectively uncovers an injury-induced developmental reversion process wherein HSCs undergo what we call a mesenchymal-to-mesothelial transition, which can be targeted to develop interventions to treat chronic liver diseases.

Chemically induced revitalization of damaged hepatocytes for regenerative liver repair.

In prolonged liver injury, hepatocytes undergo partial identity loss with decreased regenerative capacity, resulting in liver failure. Here, we identified a five compound (5C) combination that could restore hepatocyte identity and reverse the damage-associated phenotype (e.g., dysfunction, senescence, epithelial to mesenchymal transition, growth arrest, and pro-inflammatory gene expression) in damaged hepatocytes (dHeps) from CCl4-induced mice with chronic liver injury, resembling a direct chemical reprogramming approach. Systemic administration of 5C in mice with chronic liver injury promoted hepatocyte regeneration, improved liver function, and ameliorated liver fibrosis. The hepatocyte-associated transcriptional networks were reestablished with chemical treatment as revealed by motif analysis of ATAC-seq, and a hepatocyte-enriched transcription factor, Foxa2, was found to be essential for hepatocyte revitalization. Overall, our findings indicate that the phenotype and transcriptional program of dHeps can be reprogrammed to generate functional and regenerative hepatocytes by using only small molecules, as an alternative approach to liver repair and regeneration.

Cd36 is a candidate lipid sensor involved in the sensory detection of fatty acid in zebrafish.

Recently more and more evidences raise the possibility for the taste system in the role of the perception of lipids in mammals, and the fatty acid receptor CD36 has been proved to be as an important candidate receptor of fat taste. Fish has different taste modality with mammals. No information was known about the function of cd36 in fish taste till now. Here, using in situ hybridization and immunofluorescence technologies, we showed that fish cd36/Cd36 localized in taste buds. Real-time PCR technology demonstrated that, in zebrafish cd36 (zcd36)-transfected cells, linoleic acid (LA) increased the expression level of tryptophan hydroxylase-1 (TPH-1), which encodes the enzyme involved in the biosynthesis of monoamine neurotransmitter of 5-HT. Moreover, the LA-induced up-regulation expression of TPH-1 was significantly curtailed by SSO, a specific inhibitor of LCFA binding to CD36, suggesting zCd36 is implicated in the LA-induced release of neurotransmitter. Importantly, we observed that zcd36 gene knockout zebrafish reduced the preference for LA contrast to wild-type zebrafish. Together, our findings indicate that Cd36 is a candidate lipid sensor involved in the sensory detection of fatty acid in zebrafish.