Inflammation in Nonalcoholic Steatohepatitis

R Christopher Harmon; Dina G Tiniakos; Curtis K Argo

Disclosures

Expert Rev Gastroenterol Hepatol. 2011;5(2):189-200. 

In This Article

Insulin Resistance & Liver Inflammation

Nonalcoholic fatty liver disease is almost invariably associated with insulin resistance. Many NAFLD patients meet the criteria of the metabolic syndrome, all of which can be conceptually unified under the syndrome of systemic lipotoxicity.[1,25–27] In this context, NAFLD can be viewed as the hepatic manifestation of the metabolic syndrome, defined by central obesity, hypertension, hypertriglyceridemia, reduced high-density-lipoprotein cholesterol and impaired fasting glucose.

Metabolic syndrome is a state of chronic low-grade inflammation. Selective induction of a chronic inflammatory state by low-level activation of NF-κB, a transcription factor critical for the development of inflammation, in the liver of transgenic mice can induce systemic and profound hepatic insulin resistance associated with increased expression of proinflammatory cytokines, including IL-6, IL-1β and TNF-α.[28] IL-6 may play a major role in the systemic effects of insulin resistance,[28] and is also increased in NASH patients compared with patients with simple steatosis and normal controls.[29] Activation of JNK, a mitogen-activated protein kinase that plays a central role in obesity and insulin resistance, may increase hepatic inflammation and apoptosis, and in NAFLD patients is specifically associated with the presence of NASH.[30] Hepatocellular carcinoma (HCC) development, a well-established complication of advanced NAFLD, may also be partially mediated by increased release of proinflammatory and inhibitory cytokines, such as TNF-α, IL-6 and NF-κB, through a complex interplay that leads to hepatocyte death, compensatory proliferation and, eventually, carcinogenesis.[31,32]

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