Abstract
Low grade endotoxemia is a feature of obesity which is linked to development of steatohepatitis in non-alcoholic fatty liver disease. In this study, macrophages (J774) and hepatocytes (HepG2) were stimulated with lipopolysaccharide (LPS) from E. coli 0111: B4 and analyzed for modulation of this response when preconditioned or stimulated subsequent to LPS, with different doses of Vitamin D3 or docosahexaenoic acid (DHA) over a time period of 1 and 5 days. Pro-inflammatory TNFα and pro-fibrotic TGFβ released into the supernatants were measured by ELISA; qPCR was performed for Srebp-1c and PPARα mRNA (genes for products involved in fatty acid synthesis and catabolism, respectively). Vitamin D3 and DHA exerted a consistent, dose dependent anti-inflammatory effect, and increased PPARα relative to Srebp-1c in both cell types. By contrast, addition of free fatty acids (FFA, oleic acid/palmitic acid 2:1) caused aggravation of LPS-induced inflammatory reaction and an increase of Srebp-1c relative to PPARα. Our results argue in favor of dietary supplementation of Vitamin D3 or DHA (and avoidance of monounsaturated/saturated fatty acids) to alleviate development of fatty liver disease.
Highlights
Low grade endotoxemia has been detected in circumstances as diverse as a bolus of high fat diet (Erridge et al, 2007), hemodialysis (Terawaki et al, 2010), and surgery (Fujita et al, 2003)
Endotoxemia is an important factor in the progression from uncomplicated non-alcoholic fatty liver disease (NAFLD) to nonalcoholic steatohepatitis (NASH) (Finelli and Tarantino, 2014), which carries the risk of developing cirrhosis
This study analyses in parallel two TLR4 positive cell types of relevance to the liver, the macrophage and hepatocyte, for their regulation of inflammatory, fibrotic, and steatotic reactants when stimulated with Vitamin D3 or docosahexaenoic acid (DHA)
Summary
Low grade endotoxemia has been detected in circumstances as diverse as a bolus of high fat diet (Erridge et al, 2007), hemodialysis (Terawaki et al, 2010), and surgery (Fujita et al, 2003). Steatosis is the accumulation of fat in hepatocytes which can lead to an overall increase in liver size, so-called hepatomegaly. Accumulation of lipids may lead to inflammation; this is called non-alcoholic steatohepatitis, to differentiate the disease from alcohol-induced liver injury, either of which can progress to cirrhosis. Because of increasing prevalence of obesity in these populations, fatty liver disease has recently become a pediatric diagnosis (Giorgio et al, 2013). Bacterial overgrowth, increased gut Beneficial Effect of Vitamin D3 and Docosahexaenoic Acid permeability and intestinal dysmotility are characteristics of patients with non-alcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). Of note, circulating free fatty acids may function as endogenous ligands for TLR binding as so-called danger associated molecular patterns, DAMPs
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