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Deep proteomic profiling unveils arylsulfatase A as a non-alcoholic steatohepatitis inducible hepatokine and regulator of glycemic control.
Montgomery, Magdalene K; Bayliss, Jacqueline; Nie, Shuai; De Nardo, William; Keenan, Stacey N; Miotto, Paula M; Karimkhanloo, Hamzeh; Huang, Cheng; Schittenhelm, Ralf B; Don, Anthony S; Ryan, Andrew; Williamson, Nicholas A; Ooi, Geraldine J; Brown, Wendy A; Burton, Paul R; Parker, Benjamin L; Watt, Matthew J.
Affiliation
  • Montgomery MK; Department of Anatomy and Physiology, School of Biomedical Sciences, Faculty of Medicine Dentistry and Health Sciences, University of Melbourne, Melbourne, VIC, 3010, Australia. magdalene.montgomery@unimelb.edu.au.
  • Bayliss J; Department of Anatomy and Physiology, School of Biomedical Sciences, Faculty of Medicine Dentistry and Health Sciences, University of Melbourne, Melbourne, VIC, 3010, Australia.
  • Nie S; Melbourne Mass Spectrometry and Proteomics Facility, Bio21 Molecular Science & Biotechnology Institute, The University of Melbourne, Melbourne, VIC, 3010, Australia.
  • De Nardo W; Department of Anatomy and Physiology, School of Biomedical Sciences, Faculty of Medicine Dentistry and Health Sciences, University of Melbourne, Melbourne, VIC, 3010, Australia.
  • Keenan SN; Department of Anatomy and Physiology, School of Biomedical Sciences, Faculty of Medicine Dentistry and Health Sciences, University of Melbourne, Melbourne, VIC, 3010, Australia.
  • Miotto PM; Department of Anatomy and Physiology, School of Biomedical Sciences, Faculty of Medicine Dentistry and Health Sciences, University of Melbourne, Melbourne, VIC, 3010, Australia.
  • Karimkhanloo H; Department of Anatomy and Physiology, School of Biomedical Sciences, Faculty of Medicine Dentistry and Health Sciences, University of Melbourne, Melbourne, VIC, 3010, Australia.
  • Huang C; Metabolism, Diabetes and Obesity Program, Monash Biomedicine Discovery Institute, and Department of Physiology, Monash University, Melbourne, VIC, 3800, Australia.
  • Schittenhelm RB; Proteomics & Metabolomics Facility, Monash University, Melbourne, VIC, 3800, Australia.
  • Don AS; Proteomics & Metabolomics Facility, Monash University, Melbourne, VIC, 3800, Australia.
  • Ryan A; School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, 2050, Australia.
  • Williamson NA; TissuPath, Mount Waverley, VIC, 3149, Australia.
  • Ooi GJ; Melbourne Mass Spectrometry and Proteomics Facility, Bio21 Molecular Science & Biotechnology Institute, The University of Melbourne, Melbourne, VIC, 3010, Australia.
  • Brown WA; Centre for Obesity Research and Education, Department of Surgery, Monash University, Melbourne, VIC, 3004, Australia.
  • Burton PR; Centre for Obesity Research and Education, Department of Surgery, Monash University, Melbourne, VIC, 3004, Australia.
  • Parker BL; Centre for Obesity Research and Education, Department of Surgery, Monash University, Melbourne, VIC, 3004, Australia.
  • Watt MJ; Department of Anatomy and Physiology, School of Biomedical Sciences, Faculty of Medicine Dentistry and Health Sciences, University of Melbourne, Melbourne, VIC, 3010, Australia.
Nat Commun ; 13(1): 1259, 2022 03 10.
Article in En | MEDLINE | ID: mdl-35273160
ABSTRACT
Non-alcoholic steatohepatitis (NASH) and type 2 diabetes are closely linked, yet the pathophysiological mechanisms underpinning this bidirectional relationship remain unresolved. Using proteomic approaches, we interrogate hepatocyte protein secretion in two models of murine NASH to understand how liver-derived factors modulate lipid metabolism and insulin sensitivity in peripheral tissues. We reveal striking hepatokine remodelling that is associated with insulin resistance and maladaptive lipid metabolism, and identify arylsulfatase A (ARSA) as a hepatokine that is upregulated in NASH and type 2 diabetes. Mechanistically, hepatic ARSA reduces sulfatide content and increases lysophosphatidylcholine (LPC) accumulation within lipid rafts and suppresses LPC secretion from the liver, thereby lowering circulating LPC and lysophosphatidic acid (LPA) levels. Reduced LPA is linked to improvements in skeletal muscle insulin sensitivity and systemic glycemic control. Hepatic silencing of Arsa or inactivation of ARSA's enzymatic activity reverses these effects. Together, this study provides a unique resource describing global changes in hepatokine secretion in NASH, and identifies ARSA as a regulator of liver to muscle communication and as a potential therapeutic target for type 2 diabetes.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Insulin Resistance / Cerebroside-Sulfatase / Diabetes Mellitus, Type 2 / Non-alcoholic Fatty Liver Disease Type of study: Prognostic_studies Limits: Animals Language: En Journal: Nat Commun Journal subject: BIOLOGIA / CIENCIA Year: 2022 Document type: Article Affiliation country: Australia
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Insulin Resistance / Cerebroside-Sulfatase / Diabetes Mellitus, Type 2 / Non-alcoholic Fatty Liver Disease Type of study: Prognostic_studies Limits: Animals Language: En Journal: Nat Commun Journal subject: BIOLOGIA / CIENCIA Year: 2022 Document type: Article Affiliation country: Australia