Obesity depresses the anti‐inflammatory HSP70 pathway, contributing to NAFLD progression

• Published in: Obesity (Silver Spring, Md.) Vol. 23; no. 1; pp. 120 - 129
• Main Authors: Cangeri Di Naso, Fábio, Rosa Porto, Rossana, Sarubbi Fillmann, Henrique, Maggioni, Lucas, Vontobel Padoin, Alexandre, Jacques Ramos, Rafael, Corá Mottin, Claudio, Bittencourt, Aline, Anair Possa Marroni, Norma, Ivo Homem de Bittencourt, Paulo
• Format: Journal Article
• Language: English
• Published: United States Blackwell Publishing Ltd 01-01-2015
• Subjects: Adipose Tissue - metabolism; Adult; Bariatric Surgery; Binding sites; Disease Progression; Down-Regulation; Female; Gastrointestinal surgery; Hepatitis; HSP70 Heat-Shock Proteins - metabolism; Humans; Inflammation - complications; Inflammation - metabolism; Insulin; Insulin resistance; Insulin Resistance - physiology; Intra-Abdominal Fat - metabolism; Lipids; Liver cancer; Liver diseases; Liver Function Tests; Male; Metabolism; Middle Aged; Musculoskeletal system; Non-alcoholic Fatty Liver Disease - complications; Non-alcoholic Fatty Liver Disease - metabolism; Non-alcoholic Fatty Liver Disease - pathology; Non-alcoholic Fatty Liver Disease - surgery; Obesity; Obesity, Morbid - complications; Obesity, Morbid - metabolism; Obesity, Morbid - surgery; Oxidative Stress; Patients; Physiology; Proteins; Rodents; Senescence; Signal transduction; Signal Transduction - physiology
• ISSN: 1930-7381; 1930-739X
• DOI: 10.1002/oby.20919

Objectives
To evaluate whether reduced activity of the anti‐inflammatory HSP70 pathway correlates with nonalcoholic fatty liver disease (NAFLD) progression and with markers of oxidative stress because obesity activates inflammatory JNKs, whereas HSP70 exerts the opposite effect.
Methods
Adult obese patients (N = 95) undergoing bariatric surgery were divided into steatosis (ST), steatohepatitis (SH), and fibrosis (SH+F) groups. The levels of HSP70, its major transcription factor, HSF1, and JNKs were assessed by immunoblotting hepatic and visceral adipose tissue; data were confirmed by immunohistochemistry. Plasma biochemistry (lipids, HbA1c, HOMA, hepatic enzymes, and redox markers) was also evaluated.
Results
In both liver and adipose tissue, decreased HSP70 levels, paralleled by similar reductions in HSF1 and reduced plasma antioxidant enzyme activities, correlated with insulin resistance and with NAFLD progression (expression levels were as follows: ST > SH > SH + F). The immunohistochemistry results suggested Kupffer cells as a site of HSP70 inhibition. Conversely, JNK1 content and phosphorylation increased.
Conclusions
Decreased HSF1 levels in the liver and fat of obese patients correlated with impairment of HSP70 in an NAFLD stage‐dependent manner. This impairment may affect HSP70‐dependent anti‐inflammation, with consequent oxidative stress and insulin resistance in advanced stages of NAFLD. Possible causal effects of fat cell senescence are discussed.