Mineralocorticoid receptor modulation by dietary sodium influences NAFLD development in mice

Cabrera, Daniel; Rao, I. Nageswara; Raasch, Fabiola; Solı́s, Nancy; Pizarro, Margarita; Freire, Mariela; Urturi, Diego Sáenz de; Ramírez, Carolina A.; Triantafilo, Nicolás; Leon, Joel; Riquelme, Arnoldo; Barrera, Francisco; Baudrand, René; Aspichueta, Patricia; Arrese, Marco; Arab, Juan Pablo

doi:10.1016/j.aohep.2021.100357

Cited by 9 publications

(13 citation statements)

References 39 publications

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“…People with dyslipidemia and metabolic syndrome are at high risk of non-alcoholic fatty liver disease, hypertension, and cardiovascular disease, which make them important candidates for dietary sodium restriction. Results in dyslipidemic LDLr-KO mice agree with other studies in Wistar rats [6] and wild-type mice [7] that showed increased hepatic lipogenesis and dyslipidemia induced by the LS diet. However, observational data in humans associate sodium restriction with a lower odds ratio for non-alcoholic fatty liver disease [38][39][40].…”

Section: Discussionsupporting

confidence: 90%

“…It was recently demonstrated that LS intake increased hepatic diacylglycerol, esterified cholesterol, and inflammation in mice fed with a high-fat diet for 12 weeks. However, high sodium diet-fed animals were protected against steatosis induced by a high-fat or a choline/methionine deficient diet, which was ascribed to the reduced activation of the mineralocorticoid receptor helping to reduce lipogenesis markers in the liver [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

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Aerobic Exercise Training Prevents Insulin Resistance and Hepatic Lipid Accumulation in LDL Receptor Knockout Mice Chronically Fed a Low-Sodium Diet

et al. 2021

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Background: A low-sodium (LS) diet reduces blood pressure, contributing to the prevention of cardiovascular diseases. However, intense dietary sodium restriction impairs insulin sensitivity and worsens lipid profile. Considering the benefits of aerobic exercise training (AET), the effect of LS diet and AET in hepatic lipid content and gene expression was investigated in LDL receptor knockout (LDLr-KO) mice. Methods: Twelve-week-old male LDLr-KO mice fed a normal sodium (NS) or LS diet were kept sedentary (S) or trained (T) for 90 days. Body mass, plasma lipids, insulin tolerance testing, hepatic triglyceride (TG) content, gene expression, and citrate synthase (CS) activity were determined. Results were compared by 2-way ANOVA and Tukey’s post-test. Results: Compared to NS, LS increased body mass and plasma TG, and impaired insulin sensitivity, which was prevented by AET. The LS-S group, but not the LS-T group, presented greater hepatic TG than the NS-S group. The LS diet increased the expression of genes related to insulin resistance (ApocIII, G6pc, Pck1) and reduced those involved in oxidative capacity (Prkaa1, Prkaa2, Ppara, Lipe) and lipoprotein assembly (Mttp). Conclusion: AET prevented the LS-diet-induced TG accumulation in the liver by improving insulin sensitivity and the expression of insulin-regulated genes and oxidative capacity.

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Section: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Aerobic Exercise Training Prevents Insulin Resistance and Hepatic Lipid Accumulation in LDL Receptor Knockout Mice Chronically Fed a Low-Sodium Diet

et al. 2021

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“…It is possible that a high-sodium diet may indeed have a preventive effect on NAFLD. A recent animal study demonstrated that mice fed a high-sodium and high-fat diet developed less hepatic steatosis, metabolic syndrome, and insulin resistance compared with those fed a normal or low-sodium and high-fat diet [ 31 ]. The reduced steatosis was associated with lower serum aldosterone levels and downregulation of hepatic mineralocorticoid receptors; thus, decreased activation of hepatic mineralocorticoids may have resulted in beneficial downstream inhibition of lipogenesis [ 31 ].…”

Section: Discussionmentioning

confidence: 99%

“…A recent animal study demonstrated that mice fed a high-sodium and high-fat diet developed less hepatic steatosis, metabolic syndrome, and insulin resistance compared with those fed a normal or low-sodium and high-fat diet [ 31 ]. The reduced steatosis was associated with lower serum aldosterone levels and downregulation of hepatic mineralocorticoid receptors; thus, decreased activation of hepatic mineralocorticoids may have resulted in beneficial downstream inhibition of lipogenesis [ 31 ]. However, many studies have reported the opposite: a high-salt diet has been linked to increased glucocorticoid production, insulin resistance, metabolic syndrome, and NAFLD development [ 32 , 33 , 34 ].…”

Section: Discussionmentioning

confidence: 99%

Interaction between the PNPLA3 Gene and Nutritional Factors on NAFLD Development: The Korean Genome and Epidemiology Study

Lee

Chun

et al. 2022

Nutrients

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Genetic and nutritional factors contribute to the development of non-alcoholic fatty liver disease (NAFLD); however, gene–diet interactions in NAFLD development are poorly understood. In this case–control study, a large dataset from the Korean Genome and Epidemiology Study cohort (n = 72,299) comprising genomic data, medical records, social history, and dietary data was used. We investigated the interactions between the PNPLA3 rs738409 genotype and nutritional factors and their possible effect on the risk of NAFLD development in 2950 patients with NAFLD and 12,907 controls. In the PNPLA3 risk allele group, high protein, fat, sodium, phosphorus, niacin, and vitamin B6 intakes were associated with a decreased risk of NAFLD. In the non-risk allele group, only high fat intake was associated with a decreased risk of NAFLD. Among these nutrients, high sodium intake had a significant protective interaction with the PNPLA3 genotype against NAFLD (p = 0.002). Among salty foods, only kimchi had a significant protective effect against the PNPLA3 genotype (p = 0.012). Thus, the PNPLA3 genotype is differentially associated with nutritional factors. In particular, it interacts with kimchi, a fermented vegetable dish. Therefore, fermented vegetables may serve as a tailored therapeutic food for people with the PNPLA3 risk allele.

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“…In terrestrial vertebrates, most of which tend to have a low sodium intake, the MR is an important protective factor against hyponatremia [ 81 ]. Several studies support the hypothesis that excessive sodium intake, which is common in modern societies, leads to pathologically altered MR activity [ 82 , 83 , 84 , 85 ]. The fact that sodium deficiency, in contrast, protects against pathological MR activities was shown by an anthropological study on a population in the highlands of New Guinea.…”

Section: Over-active Mr In the Absence Of Elevated Aldosterone Levelsmentioning

confidence: 93%

Importance of Micromilieu for Pathophysiologic Mineralocorticoid Receptor Activity—When the Mineralocorticoid Receptor Resides in the Wrong Neighborhood

Griesler

Schuelke

Uhlig

et al. 2022

IJMS

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The mineralocorticoid receptor (MR) is a member of the steroid receptor family and acts as a ligand-dependent transcription factor. In addition to its classical effects on water and electrolyte balance, its involvement in the pathogenesis of cardiovascular and renal diseases has been the subject of research for several years. The molecular basis of the latter has not been fully elucidated, but an isolated increase in the concentration of the MR ligand aldosterone or MR expression does not suffice to explain long-term pathologic actions of the receptor. Several studies suggest that MR activity and signal transduction are modulated by the surrounding microenvironment, which therefore plays an important role in MR pathophysiological effects. Local changes in micromilieu, including hypoxia, ischemia/reperfusion, inflammation, radical stress, and aberrant salt or glucose concentrations affect MR activation and therefore may influence the probability of unphysiological MR actions. The surrounding micromilieu may modulate genomic MR activity either by causing changes in MR expression or MR activity; for example, by inducing posttranslational modifications of the MR or novel interaction with coregulators, DNA-binding sites, or non-classical pathways. This should be considered when developing treatment options and strategies for prevention of MR-associated diseases.

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Mineralocorticoid receptor modulation by dietary sodium influences NAFLD development in mice

Cited by 9 publications

References 39 publications

Aerobic Exercise Training Prevents Insulin Resistance and Hepatic Lipid Accumulation in LDL Receptor Knockout Mice Chronically Fed a Low-Sodium Diet

Aerobic Exercise Training Prevents Insulin Resistance and Hepatic Lipid Accumulation in LDL Receptor Knockout Mice Chronically Fed a Low-Sodium Diet

Interaction between the PNPLA3 Gene and Nutritional Factors on NAFLD Development: The Korean Genome and Epidemiology Study

Importance of Micromilieu for Pathophysiologic Mineralocorticoid Receptor Activity—When the Mineralocorticoid Receptor Resides in the Wrong Neighborhood

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