A vicious circle between insulin resistance and inflammation in nonalcoholic fatty liver disease

Abstract

Nonalcoholic fatty liver disease (NAFLD) comprises a spectrum of diseases, including simple steatosis, nonalcoholic steatohepatitis (NASH), liver cirrhosis and hepatocellular carcinoma. Lipotoxicity, insulin resistance (IR) and inflammation are involved in the disease process. Lipotoxicity promotes inflammation and IR, which in turn, increase adipocyte lipolysis and exacerbates lipotoxicity. Furthermore, IR and inflammation form a vicious circle, with each condition promoting the other and accelerating the development of NAFLD in the presence of lipotoxicity. As an integrator of inflammatory pathway networks, nuclear factor-kappa B (NF-κB) regulates expression of pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), and anti-inflammatory cytokines, such as adiponectin in NAFLD. In this review, the relationships between lipotoxicity, IR and inflammation in NAFLD are discussed, with particular emphasis on the inflammatory pathways.

Fig. 1

NAFLD related lipotoxicity, IR and inflammation. Legend 1: Lipotoxicity promotes inflammation and insulin resistance (IR). In turn, IR increases adipocyte lipolysis and exacerbates lipotoxicity. By binding with specific receptors, saturated fatty acids (SFAs) activate nuclear factor-kappa B (NF-κB). In IR, liver expression of NF-κB is extremely high. Receptor activator of NF-κB (RANKL) binds to its receptor (RANK) in liver and activates the NF-κB pathway. Activation of NF-κB kinase-β (IKK-β) promotes expression of pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α) and interleukin 6 (IL-6). TNF-α increases adipocyte lipolysis, strengthens phosphorylation of insulin receptor substrate-1(IRS-1) and reduces AMPK activity. IL-6 activates the c-Jun N-terminal kinase (JNK) pathway and suppresses IL-1 induced secretion of insulin. TNF-α and IL-6 promote development of IR and NAFLD. Defciency of IKK-β promotes expression of anti-inflammatory cytokines, such as adiponectin. Adiponectin receptor 1 (AdipoR1) activates AMPK activity, which then suppresses DNL, increases fatty acid oxidation and promotes mitochondrial function. AdipoR2 activates peroxisome proliferator-activated receptor-alpha (PPAR-α) signaling, which exerts anti-inflammatory effects by regulating NF-κB. Adiponectin inhibits the development of IR and NAFLD