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      Cannabinoid receptor 1 knockout alleviates hepatic steatosis by downregulating perilipin 2

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          Abstract

          The endocannabinoid (EC) system has been implicated in the pathogenesis of several metabolic diseases, including nonalcoholic fatty liver disease (NAFLD). With the current study we aimed to verify the modulatory effect of endocannabinoid receptor 1 (CB1)-signaling on perilipin 2 (PLIN2)-mediated lipophagy. Here, we demonstrate that a global knockout of the cannabinoid receptor 1 gene (CB1 −/−) reduced the expression of the lipid droplet binding protein PLIN2 in the livers of CB1 −/− and hepatitis B surface protein (HBs)-transgenic mice, which spontaneously develop hepatic steatosis. In addition, the pharmacologic activation and antagonization of CB1 in cell culture also caused an induction or reduction of PLIN2, respectively. The decreased PLIN2 expression was associated with suppressed lipogenesis and triglyceride (TG) synthesis and enhanced autophagy as shown by increased colocalization of LC3B with lysosomal-associated membrane protein 1 (LAMP1) in HBs/CB1 −/− mice. The induction of autophagy was further supported by the increased expression of LAMP1 in CB1 −/− and HBs/CB1 −/− mice. LAMP1 and PLIN2 were co-localized in HBs/CB1 −/− indicating autophagy of cytoplasmic lipid droplets (LDs) i.e., lipophagy. Lipolysis of lipid droplets was additionally indicated by elevated expression of lysosomal acid lipase. In conclusion, these results suggest that loss of CB1 signaling leads to reduced PLIN2 abundance, which triggers lipophagy. Our new findings about the association between CB1 signaling and PLIN2 may stimulate translational studies analyzing new diagnostic and therapeutic options for NAFLD.

          Abstract

          The endocannabinoid (EC) system has been implicated in the pathogenesis nonalcoholic fatty liver diseases (NAFLD). Here the authors demonstrate that endocannabinoid receptor 1 (CB1) receptor knockout in vivo and pharmacologic antagonization of CB1 in cell culture decreases expression of lipid droplet binding protein perilipin 2, which might be an essential step in lipid breakdown. Thus, pharmacologic modulation of the CB1-perilipin 2 axis might represent a novel therapeutic approach for the treatment of steatosis.

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          Efficacy and safety of the weight-loss drug rimonabant: a meta-analysis of randomised trials.

          Robin Christensen, Pernelle Kruse Kristensen, Else Marie Bartels … (2007)
          Since the prevalence of obesity continues to increase, there is a demand for effective and safe anti-obesity agents that can produce and maintain weight loss and improve comorbidity. We did a meta-analysis of all published randomised controlled trials to assess the efficacy and safety of the newly approved anti-obesity agent rimonabant. We searched The Cochrane database and Controlled Trials Register, Medline via Pubmed, Embase via WebSpirs, Web of Science, Scopus, and reference lists up to July, 2007. We collected data from four double-blind, randomised controlled trials (including 4105 participants) that compared 20 mg per day rimonabant with placebo. Patients given rimonabant had a 4.7 kg (95% CI 4.1-5.3 kg; p<0.0001) greater weight reduction after 1 year than did those given placebo. Rimonabant caused significantly more adverse events than did placebo (OR=1.4; p=0.0007; number needed to harm=25 individuals [95% CI 17-58]), and 1.4 times more serious adverse events (OR=1.4; p=0.03; number needed to harm=59 [27-830]). Patients given rimonabant were 2.5 times more likely to discontinue the treatment because of depressive mood disorders than were those given placebo (OR=2.5; p=0.01; number needed to harm=49 [19-316]). Furthermore, anxiety caused more patients to discontinue treatment in rimonabant groups than in placebo groups (OR=3.0; p=0.03; number needed to harm=166 [47-3716]). Our findings suggest that 20 mg per day rimonabant increases the risk of psychiatric adverse events--ie, depressed mood disorders and anxiety-despite depressed mood being an exclusion criterion in these trials. Taken together with the recent US Food and Drug Administration finding of increased risk of suicide during treatment with rimonabant, we recommend increased alertness by physicians to these potentially severe psychiatric adverse reactions.
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            The perilipin family of lipid droplet proteins: Gatekeepers of intracellular lipolysis.

            Carole Sztalryd, Dawn Brasaemle (2017)
            Lipid droplets in chordates are decorated by two or more members of the perilipin family of lipid droplet surface proteins. The perilipins sequester lipids by protecting lipid droplets from lipase action. Their relative expression and protective nature is adapted to the balance of lipid storage and utilization in specific cells. Most cells of the body have tiny lipid droplets with perilipins 2 and 3 at the surfaces, whereas specialized fat-storing cells with larger lipid droplets also express perilipins 1, 4, and/or 5. Perilipins 1, 2, and 5 modulate lipolysis by controlling the access of lipases and co-factors of lipases to substrate lipids stored within lipid droplets. Although perilipin 2 is relatively permissive to lipolysis, perilipins 1 and 5 have distinct control mechanisms that are altered by phosphorylation. Here we evaluate recent progress toward understanding functions of the perilipins with a focus on their role in regulating lipolysis and autophagy. This article is part of a Special Issue entitled: Recent Advances in Lipid Droplet Biology edited by Rosalind Coleman and Matthijs Hesselink.
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              Current and Future Therapeutic Regimens for Non-alcoholic Fatty Liver Disease (NAFLD) and Non-alcoholic Steatohepatitis (NASH)

              Michael Charlton, Keith D. Lindor, Zachary Goodman … (2017)
              Nonalcoholic fatty liver disease (NAFLD) and its progressive form non-alcoholic steatohepatitis (NASH), are rapidly becoming among the top causes of cirrhosis, hepatocellular carcinoma, and indications for liver transplantation. Other than lifestyle modification through diet and exercise, there are currently no other approved treatments for NASH/NAFLD. Although weight loss can be effective, it is difficult to achieve and sustain. In contrast, bariatric surgery can improve metabolic conditions associated with NAFLD, and has been shown to improve liver histology. To have approved regimens for the treatment of NASH/NAFLD, several issues must be addressed. First, all stakeholders must agree on the most appropriate clinical trial endpoints for NASH. Currently, resolution of NASH (without worsening fibrosis) or reduction of fibrosis stage (without worsening NASH) are the accepted endpoints by the regulatory authorities. It is important to recognize the prognostic implication of histologic features of NASH. In this context, although histologic NASH has been associated with advanced fibrosis, it is not an independent predictor of long-term mortality. In contrast, there are significant data to suggest that fibrosis stage is the only robust and independent predictor of liver-related mortality. In addition to the primary endpoints, several important secondary endpoints, including noninvasive biomarkers, long-term outcomes, and patient-reported outcomes must be considered. In 2018, a few phase 3 clinical trials for the treatment of NASH have been initiated. Additionally, a number of phase 2a and 2b clinical trials targeting different pathogenic pathways in NASH are in the pipeline of emerging therapies.
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                Author and article information

                Contributors
                Elke Roeb: +49 641 985 42337 , elke.roeb@innere.med.uni-giessen.de
                Journal
                Journal ID (nlm-ta): Lab Invest
                Journal ID (iso-abbrev): Lab. Invest
                Title: Laboratory Investigation; a Journal of Technical Methods and Pathology
                Publisher: Nature Publishing Group US (New York )
                ISSN (Print): 0023-6837
                ISSN (Electronic): 1530-0307
                Publication date (Electronic): 30 September 2019
                Publication date PMC-release: 30 September 2019
                Publication date (Print): 2020
                Volume: 100
                Issue: 3
                Pages: 454-465
                Affiliations
                [1 ]ISNI 0000 0001 2165 8627, GRID grid.8664.c, Department of Gastroenterology, , Justus-Liebig-University, ; Giessen, Germany
                [2 ]ISNI 0000 0004 1936 9756, GRID grid.10253.35, Institute for Surgical Research, , Philipps University of Marburg, ; Marburg, Germany
                [3 ]ISNI 0000 0001 2165 8627, GRID grid.8664.c, Institute of Medical Virology, National Reference Centre for Hepatitis B and D Viruses, , Justus-Liebig-University, ; Giessen, Germany
                [4 ]ISNI 0000 0001 2165 8627, GRID grid.8664.c, Central Biotechnical Facility, , Justus-Liebig-University, ; Giessen, Germany
                [5 ]ISNI 0000 0001 2218 4662, GRID grid.6363.0, Present Address: Department of Gastroenterology CBF, Translational Medicine Oncology, , Charité University Medicine Berlin and Bayer AG, Experimental Medicine Oncology, ; Berlin, Germany
                Author information
                http://orcid.org/0000-0002-3232-1277
                Article
                Publisher ID: 327
                DOI: 10.1038/s41374-019-0327-5
                PMC ID: 7044114
                PubMed ID: 31570772
                SO-VID: 111fe34e-f647-43a7-8c52-3e6b76432df1
                Copyright © © The Author(s) 2019
                License:

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                Date received : 15 July 2019
                Date revision received : 30 August 2019
                Date accepted : 8 September 2019
                Funding
                Funded by: FundRef https://doi.org/10.13039/501100001655, Deutscher Akademischer Austauschdienst (German Academic Exchange Service);
                Award ID: 91606935
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/100009103, Von-Behring-Röntgen-Stiftung (Von Behring-Röntgen-Foundation);
                Award ID: 60-0002
                Award ID: 58-0005
                Award Recipient :
                Categories
                Subject: Article
                Custom metadata
                issue-copyright-statement © The Author(s), under exclusive licence to United States and Canadian Academy of Pathology 2020

                ScienceOpen disciplines: Pathology
                Keywords: experimental models of disease,proteolysis
                Data availability:
                ScienceOpen disciplines: Pathology
                Keywords: experimental models of disease, proteolysis

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