Palmitic acid induces production of proinflammatory cytokine interleukin-8 from hepatocytes

Abstract

Obesity and the metabolic syndrome are closely correlated with hepatic steatosis. Simple hepatic steatosis in nonalcoholic fatty liver disease can progress to nonalcoholic steatohepatitis (NASH), which can be a precursor to more serious liver diseases, such as cirrhosis and hepatocellular carcinoma. The pathogenic mechanisms underlying progression of steatosis to NASH remain unclear; however, inflammation, proinflammatory cytokines, and oxidative stress have been postulated to play key roles. We previously reported that patients with NASH have elevated serum levels of proinflammatory cytokines, such as interleukin-8 (IL-8), which are likely to contribute to hepatic injury. This study specifically examines the effect of hepatic steatosis on IL-8 production. We induced lipid accumulation in hepatocytes (HepG2, rat primary hepatocytes, and human primary hepatocytes) by exposing them to pathophysiologically relevant concentrations of palmitic acid to simulate the excessive influx of fatty acids into hepatocytes. Significant fat accumulation was documented morphologically by Oil Red O staining in cells exposed to palmitic acid, and it was accompanied by an increase in intracellular triglyceride levels. Importantly S everal studies suggest that elevated levels of circulating free fatty acids (FFAs) contribute to the complications of obesity and the metabolic syndrome by promoting excess fat deposition in nonadipose tissues not suited for fat storage, such as the liver. 1 A strong correlation exists between obesity and fatty liver (hepatic steatosis); indeed, nonalcoholic fatty liver disease is considered to be the hepatic manifestation of the metabolic syndrome. 2 Liver steatosis is often considered a benign condition, but it can progress to nonalcoholic steatohepatitis (NASH), which may be a precursor to more severe liver diseases such as cirrhosis and hepatocellular carcinoma. 3 NASH is a common liver disease in the United States, and its prevalence is on the rise worldwide. NASH is characterized by microvesicular and macrovesicular steatosis, inflammation with mixed cellularity including neutrophils, hepatocyte degeneration and injury, and sometimes fibrosis. 3 The pathogenesis of NASH and the mechanisms of progression of hepatic steatosis to NASH remain unclear. 4 Current understanding supports the "multiple-hit model" for the development of NASH, wherein hepatic steatosis represents the "first hit," whereas the "second" or "subsequent" hits must induce liver damage and promote inflammation with neutrophil infiltration. The nature of the subsequent hits is hypothesized to include direct lipid toxicity, mitochondrial dys-

The effects of ezetimibe on non-alcoholic fatty liver disease and glucose metabolism: a randomised controlled trial

“…Ezetimibe therapy also altered the hepatic profile of fatty acid components by significantly increasing hepatic levels of lauric, myristic, palmitic, palmitoleic, margaric, stearic, oleic and linoleic acids. Experimentally, palmitate induces interleukin-8 [32], endoplasmic reticulum stress, and c-Jun amino-terminal kinase activation and promotes apoptosis in the liver [5,33,34]. Lipid-induced oxidative stress and inflammation are closely related to insulin resistance [3,5], which could be relevant to the ezetimibe-induced deterioration of glucose homeostasis.…”

Increased expression of c-Jun in nonalcoholic fatty liver disease

“…AP-1 appeared as crucial transcriptional regulator of these alterations. Saturated FFAs activate this proinflammatory transcription factor in hepatocytes, 45 and enhanced AP-1 activation has been demonstrated in obese patients with NASH. 46 AP-1 is a homo-or heterodimer consisting of proteins belonging to the c-Jun, c-Fos, ATF and JDP families, 47 with c-Jun being the best-characterized AP-1 component.…”

Necrotic foci, elevated chemokines and infiltrating neutrophils in the liver of glycogen storage disease type Ia

“…In both these conditions, that is a characteristic of IL-8-mediated neutrophil infiltration known to contribute to inflammation (19)(20)(21)(22). Lipid accumulation in hepatocytes has also been shown to stimulate IL-8 production (35). Taken together, one reasonable hypothesis is that the elevated serum IL-8 concentrations seen in GSD-Ia might signal the presence of chronic hepatic inflammation that might lead to hepatic injury.…”