Intestinal activation of the lxr-α receptor protects the liver from NASH-related damage. (March 2023)

• Record Type: Journal Article
• Authors: Lioci, G.; Gurrado, F.; Panera, N.; Braghini, M.R.; De Stefanis, C.; Alisi, A.; Svegliati-Baroni, G.
• Is Part Of: Digestive and liver disease. Volume 55(2023)Supplement 1
• Page Start: S46
• Publication Date: 2023-03
• Subjects: Digestive organs -- Diseases -- Periodicals; Liver -- Diseases -- Periodicals; 616.33005
• DOI: 10.1016/j.dld.2023.01.089
• Languages: English
• ISSNs: 1590-8658

Abstract

Abstract : Introduction: Non-Alcoholic fatty liver disease (NAFLD) is the most common liver disorder in western countries, with an estimated global prevalence of 25%, with differences according to the age, sex and ethnicity. NAFLD is characterized by the accumulation of different lipid species within hepatocytes and encompasses a spectrum of conditions including simple steatosis and non-alcoholic steatohepatitis (NASH). Liver X receptors (LXRs) are master regulators of whole-body cholesterol homeostasis and also exert anti-inflammatory effects, but its effects in the treatment of NASH are controversial. Aim: Assess in an experimental model of NAFLD, whether the activation of the LXR receptor in the intestine leads to a reduction of the damage, and in particular the accumulation of lipids and inflammation, characteristics of the metabolic syndrome. Materials and Method: We used FVBN (controls) and iVP16-LXRα (with constitutively activated LXRα in enterocytes) mice treated for 12 weeks with a control diet, or with CCl4 (Carbon tetrachloride) combined with a Western Diet (WD) as a model of NASH. Results: The results show a reduction in hepatic weight, hepatic triglyceride and cholesterol content, as well as a reduction in hepatic expression of genes involved in lipid absorption and storage and de novo lipogenesis (FABP4, CD36 and FAS) in WD/CCl4 iVP16-LXRα compared to WD/CCl4 FVBN. Also, FVBN controls showed a raised number of CD68+ macrophages compared to iVP16-LXRα WD/CCl4, suggesting an increased inflammation, unlike iVP16-LXRα which show preferentially anti-inflammatory M2 macrophages and a reduction in both systemic and hepatic inflammation (as measured by inflammatory antibody arrays and OpenArray gene expression technology). Furthermore, treated iVP16-LXRα mice showed a reduced deposition of hepatic collagen and down-expression of the main fibrogenic genes (α-SMA, TGF-β and type 1 and 3 collagen). These results indicate a possible anti-inflammatory effect exerted by HDL via the SRB1 receptor, a mechanism that needs to be further investigated. Conclusion: The present work demonstrates that a specific activation of intestinal LXRα may exert beneficial effects and could represent a novel therapy for the treatment of NASH.