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

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.

Regulation of lipid metabolism in grass carp hepatocytes by exosomes derived from fatty hepatocytes though GRP78

“…Notably, we observed a signi cant upregulation of GRP78 expression in fatty hepatocytes, leading us to speculate that GRP78 also promoted lipid accumulation in hepatocytes. Studies have demonstrated that upregulation of GRP78 contributed to insulin resistance and non-alcoholic steatohepatitis (NASH) in mice (Angelini et al, 2022), and activated the IRE1α/XBP1s signaling pathway, promoting lipid accumulation in the hepatopancreas of megalobrama amblycephala (Cao et al, 2019). Furthermore, inhibition of GRP78 has been shown to increase lipid toxicity and reactive oxygen species (ROS) generation in latency competent cancer (LCC) cells (Cook et al, 2016).…”

Intestinal heat shock proteins in metabolic syndrome: Novel mediators of obesity and its comorbidities resolution after metabolic surgery

“…Furthermore, rodent models of obesity display increased levels of GRP78 in the jejunal secretome, indicating that intestinal epithelial cells may be the primary source of GRP78 secretion in response to lipid overload. 14 …”

“…It is now widely accepted that, following cellular stress, HSPs can be released into the extracellular compartment from a variety of cells, including intestinal epithelial cells, 14 and act as a proinflammatory signal. 15 , 11 …”

SARS-CoV-2 infection and its effects on the endocrine system

“…Both CD147 and GRP78 are tumour markers [75] , [76] , indicating why cancer patients have a higher risk of severe COVID-19 [77] . Furthermore, it was recently shown that the expression of GRP78 is increased in the jejunum of rats fed a high fat diet [78] .…”