Mineralocorticoid receptor modulation by dietary sodium influences NAFLD development in mice

Ann Hepatol. 2021 Sep-Oct:24:100357. doi: 10.1016/j.aohep.2021.100357. Epub 2021 Apr 30.

Abstract

Introduction and objectives: Nonalcoholic-fatty-liver disease (NAFLD) is considered the hepatic manifestation of metabolic syndrome (MetS). Mineralocorticoid receptor (MR) activation is associated with increased risk of MetS but few studies have assessed the role of liver MR on NAFLD. We aimed to evaluate the effect of MR modulation by sodium intake in liver injury in experimental models of NAFLD.

Materials and methods: C57BL/6J mice were fed either a high-fat-diet (HFD) or a choline/methionine deficient (MCD) diet with different sodium concentrations. Hepatic concentration of lipid species, serum aldosterone levels, expression of MR, proinflammatory and profibrotic markers and liver histology were assessed.

Results: Mice fed with High-Na+/HFD showed a lower MR expression in liver (p = 0.01) and less steatosis on histology (p = 0.04). Consistently, animals from this group exhibited lower levels of serum aldosterone (p = 0.028) and lower hepatic triglyceride content (p = 0.008). This associated to a reduced expression of lipogenic genes, significant changes in lipid subspecies, lower HOMA-IR (p < 0.05), and lower expression of pro-inflammatory and profibrotic markers compared to those mice fed a Low-Na+/HFD. Additionally, mice fed a High-Na+/HFD showed higher expression of salt-inducible kinase (SIK)-1 and lower expression of serum-and-glucocorticoid-inducible kinase (SGK)-1. Similar results were observed with the MCD diet model.

Conclusion: We identified in two experimental models of NAFLD that High-Na+ diet content is associated to lower serum aldosterone levels and hepatic MR downregulation, associated to decreased steatosis and reduced de novo hepatic lipogenesis, proinflammatory and profibrotic markers. Decreased activation of hepatic MR seems to generate beneficial downstream inhibition of lipogenesis in experimental NAFLD.

Keywords: Fatty liver; Liver injury; Mineralocorticoid receptor; NAFLD; NASH; Non-alcoholic fatty liver disease; Sodium; Steatohepatitis.

MeSH terms

  • Aldosterone / blood
  • Animals
  • Diet, High-Fat
  • Disease Models, Animal
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Non-alcoholic Fatty Liver Disease / etiology
  • Non-alcoholic Fatty Liver Disease / metabolism*
  • Non-alcoholic Fatty Liver Disease / pathology
  • Receptors, Mineralocorticoid / metabolism*
  • Sodium, Dietary / administration & dosage*
  • Triglycerides / metabolism

Substances

  • Receptors, Mineralocorticoid
  • Sodium, Dietary
  • Triglycerides
  • Aldosterone