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      FAM13A Represses AMPK Activity and Regulates Hepatic Glucose and Lipid Metabolism

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          Summary

          Obesity commonly co-exists with fatty liver disease with increasing health burden worldwide. Family with Sequence Similarity 13, Member A ( FAM13A) has been associated with lipid levels and fat mass by genome-wide association studies (GWAS). However, the function of FAM13A in maintaining metabolic homeostasis in vivo remains unclear. Here, we demonstrated that rs2276936 in this locus has allelic-enhancer activity in massively parallel reporter assays (MPRA) and reporter assay. The DNA region containing rs2276936 regulates expression of endogenous FAM13A in HepG2 cells. In vivo, Fam13a −/− mice are protected from high-fat diet (HFD)-induced fatty liver accompanied by increased insulin sensitivity and reduced glucose production in liver. Mechanistically, loss of Fam13a led to the activation of AMP-activated protein kinase (AMPK) and increased mitochondrial respiration in primary hepatocytes. These findings demonstrate that FAM13A mediates obesity-related dysregulation of lipid and glucose homeostasis. Targeting FAM13A might be a promising treatment of obesity and fatty liver disease.

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          Highlights

          • •

            SNP rs2276936 regulates expression of endogenous FAM13A

          • •

            Fam13a −/− mice are protected from high-fat-diet-induced obesity and fatty liver.

          • •

            Fam13a −/− hepatocytes show increased mitochondrial respiration and AMPK activity

          Abstract

          Biological Sciences; Cell Biology; Functional Aspects of Cell Biology

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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.
          Article 0 comments Cited 125 times – based on 0 reviews     Review now
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            AMPK activation: a therapeutic target for type 2 diabetes?

            Kimberly Coughlan, Rudy J. Valentine, Neil Ruderman … (2014)
            Type 2 diabetes (T2D) is a metabolic disease characterized by insulin resistance, β-cell dysfunction, and elevated hepatic glucose output. Over 350 million people worldwide have T2D, and the International Diabetes Federation projects that this number will increase to nearly 600 million by 2035. There is a great need for more effective treatments for maintaining glucose homeostasis and improving insulin sensitivity. AMP-activated protein kinase (AMPK) is an evolutionarily conserved serine/threonine kinase whose activation elicits insulin-sensitizing effects, making it an ideal therapeutic target for T2D. AMPK is an energy-sensing enzyme that is activated when cellular energy levels are low, and it signals to stimulate glucose uptake in skeletal muscles, fatty acid oxidation in adipose (and other) tissues, and reduces hepatic glucose production. There is substantial evidence suggesting that AMPK is dysregulated in animals and humans with metabolic syndrome or T2D, and that AMPK activation (physiological or pharmacological) can improve insulin sensitivity and metabolic health. Numerous pharmacological agents, natural compounds, and hormones are known to activate AMPK, either directly or indirectly – some of which (for example, metformin and thiazolidinediones) are currently used to treat T2D. This paper will review the regulation of the AMPK pathway and its role in T2D, some of the known AMPK activators and their mechanisms of action, and the potential for future improvements in targeting AMPK for the treatment of T2D.
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              Activation of Skeletal Muscle AMPK Promotes Glucose Disposal and Glucose Lowering in Non-human Primates and Mice.

              Emily C Cokorinos, Jake Delmore, Allan R Reyes … (2017)
              The AMP-activated protein kinase (AMPK) is a potential therapeutic target for metabolic diseases based on its reported actions in the liver and skeletal muscle. We evaluated two distinct direct activators of AMPK: a non-selective activator of all AMPK complexes, PF-739, and an activator selective for AMPK β1-containing complexes, PF-249. In cells and animals, both compounds were effective at activating AMPK in hepatocytes, but only PF-739 was capable of activating AMPK in skeletal muscle. In diabetic mice, PF-739, but not PF-249, caused a rapid lowering of plasma glucose levels that was diminished in the absence of skeletal muscle, but not liver, AMPK heterotrimers and was the result of an increase in systemic glucose disposal with no impact on hepatic glucose production. Studies of PF-739 in cynomolgus monkeys confirmed translation of the glucose lowering and established activation of AMPK in skeletal muscle as a potential therapeutic approach to treat diabetic patients.
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                Author and article information

                Contributors
                Xin Lin
                Xiaobo Zhou
                Journal
                Journal ID (nlm-ta): iScience
                Journal ID (iso-abbrev): iScience
                Title: iScience
                Publisher: Elsevier
                ISSN (Electronic): 2589-0042
                Publication date PMC-release: 22 February 2020
                Publication date Collection: 27 March 2020
                Publication date (Electronic): 22 February 2020
                Volume: 23
                Issue: 3
                Electronic Location Identifier: 100928
                Affiliations
                [1 ]Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
                [2 ]Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA
                [3 ]Guangzhou First People's Hospital, the Second Affiliated Hospital of South China University of Technology, Guangzhou, Guangdong 510180, China
                [4 ]Department of Chemical and Biological Engineering, Tufts University, Boston, MA 02155, USA
                [5 ]Section of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA
                [6 ]Lineberger Comprehensive Cancer Center and Department of Biochemistry and Biophysics, School of Medicine, The University of North Carolina, Chapel Hill, NC 27514, USA
                [7 ]Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
                [8 ]School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
                Author notes
                [∗ ]Corresponding author xlin7@ 123456bwh.harvard.edu
                [∗∗ ]Corresponding author xiaobo.zhou@ 123456channing.harvard.edu
                [9]

                Lead Contact

                Article
                Publisher ID: S2589-0042(20)30112-7 Publisher ID: 100928
                DOI: 10.1016/j.isci.2020.100928
                PMC ID: 7063182
                PubMed ID: 32151973
                SO-VID: 3c94d4d2-63b2-49f9-931e-7b1650f981a2
                Copyright © © 2020 The Authors
                License:

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Date received : 15 January 2020
                Date revision received : 12 February 2020
                Date accepted : 17 February 2020
                Categories
                Subject: Article

                Keywords: biological sciences,cell biology,functional aspects of cell biology
                Data availability:
                Keywords: biological sciences, cell biology, functional aspects of cell biology

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