Role of inflammation in nonalcoholic steatohepatitis

Products of hepatic macrophages and lymphocytes are acknowledged regulators of liver injury and repair. Recent studies have identified inflammatory modulators from sources within and outside the liver that are critical to the pathogenesis and progression of chronic liver diseases, including nonalcoholic fatty liver disease. This review will focus on these developments to clarify how inflammatory mediators from adipose tissue and the liver interact to mediate the pathogenesis of nonalcoholic fatty liver disease.

Hepatic steatosis and steatohepatitis are extremely prevalent in obese individuals with the metabolic syndrome. The metabolic syndrome results from abnormal production of various adipose-derived and liver-derived factors that modulate energy substrate flux to coordinate tissue anabolism and catabolism. Individuals with the metabolic syndrome produce a relative excess of proinflammatory factors. Some factors inhibit hepatic fat disposal and promote lipid accumulation within hepatocytes. The latter induces sustained hepatic generation of proinflammatory cytokines, particularly when the hepatic innate immune system becomes Th-1 polarized. Although chronic inflammation induces production of various profibrogenic factors, progression to latter stages of nonalcoholic fatty liver disease is relatively unusual in individuals with the metabolic syndrome. This may reflect requirements for additional factors that become abundant only in individuals who have additional defects in hepatic innate immunity.

Obesity and the metabolic syndrome represent chronic inflammatory states and are associated with nonalcoholic fatty liver disease. Liver injury that ensues is dictated by metabolic and immunomodulatory factors that are produced by adipose tissue and within the liver.