Beyond the regulation of bile acid synthesis, FXR improves insulin sensitivity and glucose uptake in adipose tissue, and the liver and the skeletal muscle, by regulating metabolic genes such as PEPCK, G6Pase, and FBP1.[86] Moreover, FXR suppresses pro-inflammatory genes like interferon γ, tumor necrosis factor-α, see more and interleukin-6 by affecting NFkappaB transcriptional activity.[86, 87] However, this broad spectrum is likely to result in adverse side effects, and selective FXR agonists are required to mainly alter gene expression relevant to NASH and insulin resistance. In the MCD model of steatohepatitis, WAY-362450,

a synthetic FXR ligand, protected against hepatic inflammation and fibrosis without inhibiting hepatic triglyceride accumulation.[88] this website Currently, obeticholic acid, a semi-synthetic bile acid derivative, is tested in patients with biopsy-proven NASH (ClinicalTrials.gov Identifier: NCT01265498).[86] An unwanted side effect of obeticholic acid is exacerbation of itching. A pro-inflammatory intestinal microbiome has been observed in mice and patients with NASH.[37-39, 41] In a model of genetic dyslipidemia

using ApoE-deficient mice, supplementation of the probiotic VSL#3 that contains different lactobacilli and bifidobacteria improved insulin signaling in hepatocytes and ameliorated adipose tissue inflammation,[89] and the supplementation of lactobacillus casei shirota protected Chloroambucil mice from increased activation of TLR4 and hepatic steatosis induced by a high-fructose diet.[90] In an open-label pilot study in 20 patients with biopsy-proven NASH, supplementation of a probiotic containing lactobacilli and bifidobacteria

over 6 months improved hepatic steatosis, as determined by MRI and serum transaminases.[91] Together with the human randomized controlled study on fecal transplantation of a healthy microbiota in patients with insulin resistance,[42] these recent reports support the role of microbiota in the pathogenesis of insulin resistance and NASH, partly by reducing bacterial inflammatory triggers and nutrient extractions and modification. It also hints to a role of prebiotics, that is nutrients that favor the growth of certain bacterial species, that may likely play in the treatment of obesity and NASH.[92] NAFLD has become a global challenge to our health-care systems. Changes in lifestyle and nutrition have put large parts of the population at risk of developing NASH, cirrhosis, and liver cancer. In contrast to other liver diseases with emerging therapeutic options, and despite the benefit of lifestyle changes, NAFLD will remain a great health problem necessitating (adjunctive) pharmacological therapies. Moreover, given the unpredictable course of this common disease, improved non-invasive biomarkers are urgently needed to better assess NAFLD/NASH activity and fibrosis, and to speed up drug development.