Upper gut heat shock proteins HSP70 and GRP78 promote insulin resistance, hyperglycemia, and non-alcoholic steatohepatitis

Giulia Angelini, Lidia Castagneto-Gissey, Serenella Salinari, Alessandro Bertuzzi, Danila Anello, Meenakshi Pradhan, Marlen Zschätzsch, Paul Ritter, Carel W. Le Roux, Francesco Rubino, Nicola Basso, Giovanni Casella, Stefan R. Bornstein, Valentina Tremaroli and Geltrude Mingrone ()
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Giulia Angelini: Università Cattolica del Sacro Cuore
Lidia Castagneto-Gissey: Sapienza University of Rome
Serenella Salinari: University of Rome “Sapienza”
Alessandro Bertuzzi: CNR-Institute of Systems Analysis and Computer Science (IASI)
Danila Anello: Università Cattolica del Sacro Cuore
Meenakshi Pradhan: University of Gothenburg
Marlen Zschätzsch: Technischen Universität Dresden
Paul Ritter: Bruker Daltonics SPR
Carel W. Le Roux: University College Dublin
Francesco Rubino: Bariatric and Metabolic Surgery; King’s College Hospital
Nicola Basso: Sapienza University of Rome
Giovanni Casella: Sapienza University of Rome
Stefan R. Bornstein: Universitätsklinikum Carl Gustav Carus an der Technischen Universität Dresden
Valentina Tremaroli: University of Gothenburg
Geltrude Mingrone: Università Cattolica del Sacro Cuore

Nature Communications, 2022, vol. 13, issue 1, 1-21

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-35310-5

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