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Single cell RNA-seq of liver cells from B6J mice fed a chow or a high-fat-and-high-sucrose diet

ABSTRACT: Cannabinoid receptor-1 (CB-1) blockage in brain is responsible for weight loss, many of the metabolic benefits associated with CB-1 blockade have been attributed to inhibition of CB-1 signaling in the periphery. We produced mice that lacked CB-1 receptors in hepatocytes or stellate cells to determine if CB-1 signaling contributes to the development of NAFLD or liver fibrosis. Deletion of CB-1 receptors in hepatocytes did not alter the development of NAFLD in mice fed a high sucrose high fat diet (HSD) or high fat diet (HFD). Similarly, deletion of CB-1 deletion specifically in stellate cells also did not prevent the development of NAFLD in mice fed the HFD nor did it protect mice for carbon tetrachloride-induced fibrosis. To determine if a small population of cells in liver express CB-1 at high levels either before and/or after HSD feeding, here we performed single cell RNA-sequencing of livers from wild-type mice fed chow or a HSD for 17 weeks and analyzed CB-1 expression. Single-cell sequencing of hepatocytes and stellate cells reveals low Cnr1 expression in livers of mice fed a chow or HSD. Combined, these studies do not support a direct role for hepatocyte or stellate cell CB-1 signaling in the development of NAFLD or liver fibrosis.

ORGANISM(S): Mus musculus

PROVIDER: GSE182365 | GEO | 2021/09/01

REPOSITORIES: GEO

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Project description:Background: Senescent hepatocytes accumulate in parallel with fibrosis progression during NASH. The mechanisms that enable progressive expansion of nonreplicating cell populations and the significance of that process in determining NASH outcomes are unclear. Many types of senescing cells upregulate the THBD-PAR-1 signaling axis to remain viable. Vorapaxar, an FDA-approved PAR-1 inhibitor, blocks the activity of that pathway. We used vorapaxar to determine if and how THBD-PAR1 signaling promotes fibrosis progression in NASH. Methods: We evaluated the THBD-PAR1 pathway in liver biopsies from NAFLD patient cohorts with a spectrum of liver fibrosis. Chow fed mice were treated with viral vectors to over-express p16 specifically in hepatocytes and induce replicative senescence. Effects on the THBD-PAR-1 axis and regenerative capacity were assessed; the transcriptome of p16 over-expressing hepatocytes was characterized and we examined how conditioned medium from senescent but viable (dubbed ‘undead’) hepatocytes reprograms hepatic stellate cells. A genetically obese mouse model of NASH with little liver fibrosis, and a diet-induced mouse model of NASH with advanced fibrosis were treated with vorapaxar to determine effects on hepatocyte senescence and liver damage. Results: Inducing senescence up-regulates the THBD-PAR1 signaling axis in hepatocytes and induces their expression of fibrogenic factors, including hedgehog ligands. Hepatocyte THBD-PAR1 signaling increases in NAFLD and supports sustained hepatocyte senescence that limits effective liver regeneration and promotes maladaptive repair. Inhibiting PAR-1 signaling with vorapaxar interrupts this process, reduces the burden of ‘undead’ senescent cells, and safely improves NASH and fibrosis despite ongoing lipotoxic stress Conclusion: The THBD-PAR1 signaling axis is a novel therapeutic target for NASH because blocking this pathway prevents accumulation of senescing but viable hepatocytes that generate factors that promote maladaptive liver repair.

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Single cell RNA-seq of liver cells from B6J mice fed a chow or a high-fat-and-high-sucrose diet

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