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

Abstract

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.

• Authors: Fábio Cangeri Di Naso, Rossana Rosa Porto, Henrique Sarubbi Fillmann, Lucas Maggioni, Alexandre Vontobel Padoin, Rafael Jacques Ramos, Claudio Corá Mottin, Aline Bittencourt, Norma Anair Possa Marroni, Paulo Ivo Homem de Bittencourt Jr
• Journal: Obesity (Silver Spring, Md.) (Obesity (Silver Spring)) Vol. 23 Issue 1 Pg. 120-9 (Jan 2015) ISSN: 1930-739X [Electronic] United States
• PMID: 25292174 (Publication Type: Clinical Trial, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 The Obesity Society.

Chemical References

• HSP70 Heat-Shock Proteins

Topics

• Adipose Tissue (metabolism)
• Adult
• Bariatric Surgery
• Disease Progression
• Down-Regulation
• Female
• HSP70 Heat-Shock Proteins (metabolism)
• Humans
• Inflammation (complications, metabolism)
• Insulin Resistance (physiology)
• Intra-Abdominal Fat (metabolism)
• Liver Function Tests
• Male
• Middle Aged
• Non-alcoholic Fatty Liver Disease (complications, metabolism, pathology, surgery)
• Obesity, Morbid (complications, metabolism, surgery)
• Oxidative Stress
• Signal Transduction (physiology)