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Original Article
DOI: 10.1016/j.aohep.2021.100357
Open Access
Pre-proof, online 1 May 2021
Mineralocorticoid receptor modulation by dietary sodium influences NAFLD development in mice
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Daniel Cabrera1,2, Isabel Rao1, Fabiola Raasch1, Nancy Solis1, Margarita Pizarro1, Mariela Freire1, Diego Sáenz De Urturi3, Carolina A Ramírez4, Nicolás Triantafilo5, Jonathan León1, Arnoldo Riquelme1,6, Francisco Barrera1, Rene Baudrand7, Patricia Aspichueta3,8, Marco Arrese1,9,
Corresponding author
marrese@med.puc.cl

Corresponding authors: Pontificia Universidad Católica de Chile, Departamento de Gastroenterología, Facultad de Medicina, Marcoleta 367, Santiago 8330024, CHILE
, Juan P Arab1,9,
Corresponding author
jparab@uc.cl

Corresponding authors: Pontificia Universidad Católica de Chile, Departamento de Gastroenterología, Facultad de Medicina, Marcoleta 367, Santiago 8330024, CHILE
1 Departamento de Gastroenterologia, Escuela de Medicina, Pontificia Universidad Catolica de Chile, Santiago, Chile
2 Facultad de Ciencias Médicas, Universidad Bernardo O Higgins, Santiago, Chile
3 Department of Physiology, University of the Basque Country UPV/EHU, Leioa, Spain
4 Departamento de Anestesiología, Clínica Las Condes, Santiago, Chile
5 Departamento de Hematologia, Escuela de Medicina, Pontificia Universidad Catolica de Chile, Santiago, Chile
6 Departamento de Ciencias de la Salud, Facultad de Medicina, Pontificia Universidad Catolica de Chile, Santiago, Chile
7 Departamento de Endocrinologia, Escuela de Medicina, Pontificia Universidad Catolica de Chile, Santiago, Chile
8 Biocruces Health Research Institute, Spain
9 Centro de Envejecimiento y Regeneracion (CARE), Departamento de Biologia Celular y Molecular, Facultad de Ciencias Biologicas Pontificia Universidad Catolica de Chile, Santiago, Chile
Article information
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:
non-alcoholic fatty liver disease
NAFLD
NASH
steatohepatitis
fatty liver
mineralocorticoid receptor
sodium
liver injury
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Copyright © 2021. Fundación Clínica Médica Sur, A.C.
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