Abstract
Although previous studies have indicated important roles of palmitate, a saturated fatty acid, in the pathogenesis of nonalcoholic fatty liver disease (NAFLD), it remains unclear how palmitate contributes to inflammation and fibrosis in the liver. Administration of palmitate in high fat diet (HFD)-fed but not basal diet (BD)-fed mice resulted in an increase in serum alanine aminotransferase (ALT) levels. Surprisingly, combined administration of very low dose lipopolysaccharide in palmitate-treated mice led to a marked increase in serum ALT levels despite BD-fed conditions. Administration of palmitate alone in BD-fed mice caused inflammatory cell infiltration and liver fibrosis mediated by the toll-like receptor 4 pathway without ALT elevation. In addition, a significant correlation between serum free fatty acid levels and liver fibrosis stage was observed in patients with NAFLD. These results indicate that palmitate may play crucial roles in the pathogenesis of NAFLD in the presence of gut-derived endotoxin.
Highlights
Previous studies have indicated important roles of palmitate, a saturated fatty acid, in the pathogenesis of nonalcoholic fatty liver disease (NAFLD), it remains unclear how palmitate contributes to inflammation and fibrosis in the liver
The elevation in serum ALT levels was observed in high fat diet (HFD)-fed but not basal diet (BD)-fed mice, the number of infiltrated neutrophils and macrophages to hepatocytes was similar between BD-fed and HFD-fed mice (Fig. 1A–D)
We showed that (1) palmitate, a saturated fatty acid, elevated serum ALT levels in the presence of gut-derived endotoxin, (2) palmitate induced inflammatory cell infiltration in the liver by up-regulation of chemokines and stimulated mild liver fibrosis via the toll-like receptor 4 (TLR4) pathway despite the absence of endotoxin, (3) palmitate lipotoxicity cooperated with gut-derived endotoxin in liver inflammation, and (4) fibrosis was confirmed in patients with NAFLD (Fig. 6)
Summary
Palmitate induced neutrophil and macrophage infiltration in the liver. Three hours after a single intraperitoneal injection of emulsified ethyl palmitate, serum FFA levels were significantly increased compared with those of untreated or vehicle-treated mice both under BD-fed and HFD-fed conditions (Fig. S1A). We found that saturated fatty acids, palmitate, induced neutrophil and macrophage infiltrations in the liver because of increased Cxcl[2] and Ccl[2] mRNA expression compared with monounsaturated fatty acids (Figs S1E,F and S3C,D) These results suggest that palmitate induces liver inflammation more effectively than other fatty acids. We depleted the number of macrophages using clodronate liposomes and found that the αSMA-positive area upregulated by palmitate injection was similar between the clodronate and control liposome-treated mice following BD and HFD feeding (Fig. 4F) These results suggest that HSCs are activated by palmitate without macrophages or neutrophils in vivo. These results suggest that serum FFAs promote liver fibrosis in patients with NAFLD
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