Increased hepatic and circulating interleukin-6 levels in human nonalcoholic steatohepatitis.
BACKGROUND
Nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D) are growing public health problems, and are strongly associated. The link between the two conditions remains poorly understood. Hepatic interleukin-6 (IL-6), a major proinflammatory cytokine, expression is increased in animal models of NAFLD, while in mice, selective sustained upregulation of IL-6 in the liver results in systemic insulin resistance. The extent and clinical significance of hepatic IL-6 expression in human NAFLD, as well as potential mechanisms by which steatosis may increase IL-6 production in the liver, have not been examined.


OBJECTIVE
To ascertain the occurrence and significance of IL-6 expression in the liver in human NAFLD.


METHODS
Plasma was obtained at time of liver biopsy from 50 consecutive patients with suspected NAFLD. Histology was assessed blindly. Hepatic IL-6 expression was assessed by immunohistochemistry, while plasma IL-6 levels were determined by an enzyme-linked immunosorbent assay.


RESULTS
IL-6 expression was markedly increased in the livers of patients with nonalcoholic steatohepatitis (NASH) as compared to patients with simple steatosis (P < 0.005) or normal biopsies (P < 0.010), confirming the presence of hepatic IL-6 expression in human NASH. A positive correlation was observed between hepatocyte IL-6 expression and degree of inflammation and stage of fibrosis. Furthermore, liver IL-6 expression positively correlated with plasma IL-6 levels and degree of systemic insulin resistance. Culture of liver cells with saturated, but not mono- or polyunsaturated, FFA resulted in a significant increase in IL-6 messenger RNA (mRNA) and protein expression.


CONCLUSIONS
Collectively, these data suggest that increased hepatic IL-6 production may play an important role in NASH development, as well as in systemic insulin resistance and diabetes.
Department of Gastroenterology and Hepatology, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
Anna
A
Wieckowska
Bettina G
BG
Papouchado
ZhengZheng
Z
Li
Rocio
R
Lopez
Nizar N
NN
Zein
Ariel E
AE
Feldstein
D000328:Adult; D016022:Case-Control Studies; D015331:Cohort Studies; D005230:Fatty Acids, Nonesterified / Q000502:physiology; D005234:Fatty Liver / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006505:Hepatitis / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology; D015850:Interleukin-6 / Q000378:metabolism*; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D012720:Severity of Illness Index
D005230:Fatty Acids, Nonesterified; D015850:Interleukin-6