Cannabinoid receptor 1 signaling in hepatocytes and stellate cells does not contribute to NAFLD
Simeng Wang, Qingzhang Zhu, Guosheng Liang, Tania Franks, Magalie Boucher, Kendra K. Bence, Mingjian Lu, Carlos M. Castorena, Shangang Zhao, Joel K. Elmquist, Philipp E. Scherer, Jay D. Horton
Simeng Wang, Qingzhang Zhu, Guosheng Liang, Tania Franks, Magalie Boucher, Kendra K. Bence, Mingjian Lu, Carlos M. Castorena, Shangang Zhao, Joel K. Elmquist, Philipp E. Scherer, Jay D. Horton
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Research Article Hepatology Metabolism

Cannabinoid receptor 1 signaling in hepatocytes and stellate cells does not contribute to NAFLD

Abstract

The endocannabinoid system regulates appetite and energy expenditure and inhibitors of cannabinoid receptor 1 (CB-1) induce weight loss with improvement in components of the metabolic syndrome. While 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. As a result, there has been interest in developing a peripherally restricted CB-1 inhibitor for the treatment of nonalcoholic fatty liver disease (NAFLD) that would lack the unwanted centrally mediated side effects. Here, we produced mice that lacked CB-1 in hepatocytes or stellate cells to determine if CB-1 signaling contributes to the development of NAFLD or liver fibrosis. Deletion of CB-1 in hepatocytes did not alter the development of NAFLD in mice fed a high-sucrose diet (HSD) or a high-fat diet (HFD). Similarly, deletion of CB-1 specifically in stellate cells also did not prevent the development of NAFLD in mice fed the HFD, nor did it protect mice from carbon tetrachloride–induced fibrosis. 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.

Authors

Simeng Wang, Qingzhang Zhu, Guosheng Liang, Tania Franks, Magalie Boucher, Kendra K. Bence, Mingjian Lu, Carlos M. Castorena, Shangang Zhao, Joel K. Elmquist, Philipp E. Scherer, Jay D. Horton

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Figure 1

Cnr1 deletion in hepatocytes does not affect body weight, liver function, or diet-induced obesity in 22-week-old mice fed chow or an HSD.

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Cnr1 deletion in hepatocytes does not affect body weight, liver functio...
Growth curves of chow-fed (A) and HSD-fed (B) Cnr1fl/fl and Hep-Cnr1–/– mice (n = 6–8/group). Body weights were monitored weekly starting at 5 weeks of age. (C) Plasma ALT and AST levels. (D) Whole-liver RNA was extracted for measurement of relative mRNA levels of Cnr1, Col1a1, Lrat, and Acta2 (αSMA) quantified by qPCR. ApoB was used as an invariant control. Values are expressed relative to chow-fed Cnr1fl/fl mice, which was arbitrarily set to 1. Corresponding mean Ct values are denoted above. (E) Mean area of collagen was obtained by calculating the PSR-stained red area in the image under a split green channel, as described in the Methods. Results shown as mean ± SEM, assessed by ANOVA. (F) H&E, trichrome, and PSR staining of liver sections. Scale bar: 100 μm . All experiments (A–F) were repeated with a separate cohort of mice and with similar results.