title: RABL2 Is Required for Hepatic Fatty Acid Homeostasis and Its Dysfunction Leads to Steatosis and a Diabetes-Like State.
abstract: Fatty liver, or hepatic steatosis, is an alarmingly common pathology in western societies, in large part because if left unheeded, it can lead to life-threatening forms of nonalcoholic fatty liver disease, including nonalcoholic steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. As such, it is essential that we attain a greater understanding of the pathways that control energy partitioning in the liver and ultimately how they are impacted by environmental factors. Here, we define the essential requirement for a member of the Ras-related protein in the brain (RAB)-like (RABL) clade of small GTPases, RABL2, in fatty acid metabolism including in microtubule-associated mitochondrial movement within the liver. RABL2 dysfunction, even in mice fed a low-fat chow diet, leads to retarded hepatic mitochondria movement associated with and a cascading phenotype of interrelated metabolic defects reminiscent of a type 2 diabetic state: hepatic steatosis, insulin resistance, glucose intolerance, and adult onset obesity. RABL2 dysfunction does not, however, alter mitochondrial content, or the inherent respiratory capacity of individual mitochondria per se. Rather, it is associated with a decreased capacity for fatty oxidation in the context of the intact cell, suggesting a complex, and important, role for mitochondrial movement in metabolic health. Our data highlight the importance of RABL2 and mitochondrial dynamics in hepatic fatty acid oxidation and in the achievement of metabolic balance.
authors.affiliation: The Development and Stem Cells Program of the Biomedicine Discovery Institute and Department of Anatomy and Developmental Biology (J.C.Y.L., A.E.O., M.K.O.), The Obesity and Metabolism Program of the Biomedicine Discovery Institute (J.C.Y.L., Z.B.A., T.T., M.J.W.), Departments of Physiology (J.C.Y.L., Z.B.A., M.J.W.) and Biochemistry and Molecular Biology (T.T.), and Monash Micro Imaging (C.L.), Monash University, Victoria 3800, Australia.
authors.forename: Jennifer Chi
authors.initials: JC
authors.lastname: Yi Lo
authors.affiliation: The Development and Stem Cells Program of the Biomedicine Discovery Institute and Department of Anatomy and Developmental Biology (J.C.Y.L., A.E.O., M.K.O.), The Obesity and Metabolism Program of the Biomedicine Discovery Institute (J.C.Y.L., Z.B.A., T.T., M.J.W.), Departments of Physiology (J.C.Y.L., Z.B.A., M.J.W.) and Biochemistry and Molecular Biology (T.T.), and Monash Micro Imaging (C.L.), Monash University, Victoria 3800, Australia.
authors.forename: Anne E
authors.initials: AE
authors.lastname: O'Connor
authors.affiliation: The Development and Stem Cells Program of the Biomedicine Discovery Institute and Department of Anatomy and Developmental Biology (J.C.Y.L., A.E.O., M.K.O.), The Obesity and Metabolism Program of the Biomedicine Discovery Institute (J.C.Y.L., Z.B.A., T.T., M.J.W.), Departments of Physiology (J.C.Y.L., Z.B.A., M.J.W.) and Biochemistry and Molecular Biology (T.T.), and Monash Micro Imaging (C.L.), Monash University, Victoria 3800, Australia.
authors.forename: Zane B
authors.initials: ZB
authors.lastname: Andrews
authors.affiliation: The Development and Stem Cells Program of the Biomedicine Discovery Institute and Department of Anatomy and Developmental Biology (J.C.Y.L., A.E.O., M.K.O.), The Obesity and Metabolism Program of the Biomedicine Discovery Institute (J.C.Y.L., Z.B.A., T.T., M.J.W.), Departments of Physiology (J.C.Y.L., Z.B.A., M.J.W.) and Biochemistry and Molecular Biology (T.T.), and Monash Micro Imaging (C.L.), Monash University, Victoria 3800, Australia.
authors.forename: Camden
authors.initials: C
authors.lastname: Lo
authors.affiliation: The Development and Stem Cells Program of the Biomedicine Discovery Institute and Department of Anatomy and Developmental Biology (J.C.Y.L., A.E.O., M.K.O.), The Obesity and Metabolism Program of the Biomedicine Discovery Institute (J.C.Y.L., Z.B.A., T.T., M.J.W.), Departments of Physiology (J.C.Y.L., Z.B.A., M.J.W.) and Biochemistry and Molecular Biology (T.T.), and Monash Micro Imaging (C.L.), Monash University, Victoria 3800, Australia.
authors.forename: Tony
authors.initials: T
authors.lastname: Tiganis
authors.affiliation: The Development and Stem Cells Program of the Biomedicine Discovery Institute and Department of Anatomy and Developmental Biology (J.C.Y.L., A.E.O., M.K.O.), The Obesity and Metabolism Program of the Biomedicine Discovery Institute (J.C.Y.L., Z.B.A., T.T., M.J.W.), Departments of Physiology (J.C.Y.L., Z.B.A., M.J.W.) and Biochemistry and Molecular Biology (T.T.), and Monash Micro Imaging (C.L.), Monash University, Victoria 3800, Australia.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Watt
authors.affiliation: The Development and Stem Cells Program of the Biomedicine Discovery Institute and Department of Anatomy and Developmental Biology (J.C.Y.L., A.E.O., M.K.O.), The Obesity and Metabolism Program of the Biomedicine Discovery Institute (J.C.Y.L., Z.B.A., T.T., M.J.W.), Departments of Physiology (J.C.Y.L., Z.B.A., M.J.W.) and Biochemistry and Molecular Biology (T.T.), and Monash Micro Imaging (C.L.), Monash University, Victoria 3800, Australia.
authors.forename: Moira K
authors.initials: MK
authors.lastname: O'Bryan
mesh_terms: D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism*; D005234:Fatty Liver / Q000235:genetics / Q000378:metabolism*; D018149:Glucose Intolerance / Q000235:genetics / Q000378:metabolism; D006706:Homeostasis / Q000502:physiology; D007333:Insulin Resistance / Q000235:genetics*; D050356:Lipid Metabolism / Q000235:genetics*; D050155:Lipogenesis / Q000235:genetics; D008099:Liver / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D009765:Obesity / Q000235:genetics / Q000378:metabolism; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C579026:RABL2 protein, mouse; D020691:rab GTP-Binding Proteins