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.
Wieckowska
Anna
A
Department of Gastroenterology and Hepatology, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
Papouchado
Bettina G
BG
Li
ZhengZheng
Z
Lopez
Rocio
R
Zein
Nizar N
NN
Feldstein
Ariel E
AE
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