title: Obesity depresses the anti-inflammatory HSP70 pathway, contributing to NAFLD progression.
abstract: OBJECTIVE
  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.affiliation: Laboratory of Physiology and Experimental Hepatology, Porto Alegre Clinics Hospital, Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, Brazil.
authors.forename: Fábio Cangeri
authors.initials: FC
authors.lastname: Di Naso
authors.forename: Rossana Rosa
authors.initials: RR
authors.lastname: Porto
authors.forename: Henrique Sarubbi
authors.initials: HS
authors.lastname: Fillmann
authors.forename: Lucas
authors.initials: L
authors.lastname: Maggioni
authors.forename: Alexandre Vontobel
authors.initials: AV
authors.lastname: Padoin
authors.forename: Rafael Jacques
authors.initials: RJ
authors.lastname: Ramos
authors.forename: Claudio Corá
authors.initials: CC
authors.lastname: Mottin
authors.forename: Aline
authors.initials: A
authors.lastname: Bittencourt
authors.forename: Norma Anair Possa
authors.initials: NA
authors.lastname: Marroni
authors.forename: Paulo Ivo Homem
authors.initials: PI
authors.lastname: de Bittencourt
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000328:Adult; D050110:Bariatric Surgery; D018450:Disease Progression; D015536:Down-Regulation; D005260:Female; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000150:complications / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology; D050152:Intra-Abdominal Fat / Q000378:metabolism; D008111:Liver Function Tests; D008297:Male; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease / Q000150:complications / Q000378:metabolism* / Q000473:pathology* / Q000601:surgery; D009767:Obesity, Morbid / Q000150:complications / Q000378:metabolism* / Q000601:surgery; D018384:Oxidative Stress; D015398:Signal Transduction / Q000502:physiology
chemical_list: D018840:HSP70 Heat-Shock Proteins