Obesity and elevated fasting glucose remain crucial risk factors for nonalcoholic fatty liver disease. Increased adiposity and insulin resistance can progress NASH to fibrosis by developing a profibrotic mileau in the liver, with increased hepatocellular death, increased reactive oxygen species generation, and an altered adipokine/cytokine balance. 

Animal models and population-based studies hint at a causal link between excess fat accumulation, insulin resistance, and progression to fibrosis. 

Recent studies explain the mechanisms of obesity-induced insulin resistance and its association with liver fibrosis as a complex cross-talk between adipose tissue and liver through adipokines and inflammatory cytokines. Adipose tissue produces adipokines and inflammatory cytokines, which may promote hepatic insulin resistance and progression of NAFLD. 

Besides, hepatic steatosis, in the setting of secondary or superimposed liver injury such as in alcohol abusers, may further progress liver fibrosis. Activation of the JNK-1 pathway is pivotal in the pathogenesis of obesity-induced insulin resistance. 

Excess hepatic triglycerides and oxidative stress may injure tissue and activate repair mechanisms, which involve recruitment of immune cells, angiogenesis, activation of Hepatic stellate cells (HSC), and subsequent extracellular matrix (ECM) deposition. 

Weight loss is the foundation of current NAFLD management. Recent studies have reported newer pharmacological interventions targeting the fibrogenesis pathway, including the JNK-1 signaling pathway, antiangiogenic agents, cytokines and their receptors, and the adenosine receptor pathway. The modulation of HSC activation and ECM remodeling for NAFLD prevention and treatment is currently under investigation.

Source: Chiang DJ, Pritchard MT, Nagy LE. Obesity, diabetes mellitus, and liver fibrosis, American Journal of Physiology-Gastrointestinal and Liver Physiology, 2011;300(5): G697-G702. https://doi.org/10.1152/ajpgi.00426.2010