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Abstract Details
Upper gut heat shock proteins HSP70 and GRP78 promote insulin resistance, hyperglycemia, and non-alcoholic steatohepatitis
Nat Commun. 2022 Dec 13;13(1):7715. doi: 10.1038/s41467-022-35310-5.
1Università Cattolica del Sacro Cuore, Rome, Italy.
2Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.
3Department of Surgical Sciences, Sapienza University of Rome, Rome, Italy.
4Department of Computer, Control, and Management Engineering "Antonio Ruberti", University of Rome "Sapienza", Rome, Italy.
5CNR-Institute of Systems Analysis and Computer Science (IASI), Rome, Italy.
6Wallenberg Laboratory for Cardiovascular and Metabolic Research, Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden.
7Institute of Natural Materials Technology, Faculty of Mechanical Science and Engineering, Technischen Universität Dresden, Dresden, Germany.
8Biotopa gGmbH, Dresden, Germany.
9Bruker Daltonics SPR, Hamburg, Germany.
10Diabetes Complications Research Centre, Conway Institute, University College Dublin, Dublin, Ireland.
11Bariatric and Metabolic Surgery; King's College Hospital, London, UK.
12Department of Medicine III, Universitätsklinikum Carl Gustav Carus an der Technischen Universität Dresden, Dresden, Germany.
13Division of Diabetes & Nutritional Sciences, School of Cardiovascular and Metabolic Medicine & Sciences, King's College London, London, UK.
14Università Cattolica del Sacro Cuore, Rome, Italy. geltrude.mingrone@kcl.ac.uk.
15Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy. geltrude.mingrone@kcl.ac.uk.
16Division of Diabetes & Nutritional Sciences, School of Cardiovascular and Metabolic Medicine & Sciences, King's College London, London, UK. geltrude.mingrone@kcl.ac.uk.
Abstract
A high-fat diet increases the risk of insulin resistance, type-2 diabetes, and non-alcoholic steato-hepatitis. Here we identified two heat-shock proteins, Heat-Shock-Protein70 and Glucose-Regulated Protein78, which are increased in the jejunum of rats on a high-fat diet. We demonstrated a causal link between these proteins and hepatic and whole-body insulin-resistance, as well as the metabolic response to bariatric/metabolic surgery. Long-term continuous infusion of Heat-Shock-Protein70 and Glucose-Regulated Protein78 caused insulin-resistance, hyperglycemia, and non-alcoholic steato-hepatitis in rats on a chow diet, while in rats on a high-fat diet continuous infusion of monoclonal antibodies reversed these phenotypes, mimicking metabolic surgery. Infusion of these proteins or their antibodies was also associated with shifts in fecal microbiota composition. Serum levels of Heat-Shock-Protein70 and Glucose-Regulated Protein78were elevated in patients with non-alcoholic steato-hepatitis, but decreased following metabolic surgery. Understanding the intestinal regulation of metabolism may provide options to reverse metabolic diseases.