Salt-Induced Hepatic Inflammatory Memory Contributes to Cardiovascular Damage Through Epigenetic Modulation of SIRT3

Abstract

Background: High salt intake is the leading dietary risk factor for cardiovascular diseases. Although clinical evidence suggests that high salt intake is associated with nonalcoholic fatty liver disease, which is an independent risk factor for cardiovascular diseases, it remains elusive whether salt-induced hepatic damage leads to the development of cardiovascular diseases. Methods: Mice were fed with normal or high-salt diet for 8 weeks to determine the effect of salt loading on liver histological changes and blood pressure, and salt withdrawal and metformin treatment were also conducted on some high-salt diet–fed mice. Adeno-associated virus 8, global knockout, or tissue-specific knockout mice were used to manipulate the expression of some target genes in vivo, including SIRT3 (sirtuin 3), NRF2 (NF-E2-related factor 2), and AMPK (AMP-activated protein kinase). Results: Mice fed with a high-salt diet displayed obvious hepatic steatosis and inflammation, accompanied with hypertension and cardiac dysfunction. All these pathological changes persisted after salt withdrawal, displaying a memory phenomenon. Gene expression analysis and phenotypes of SIRT3 knockout mice revealed that reduced expression of SIRT3 was a chief culprit responsible for the persistent inflammation in the liver, and recovering SIRT3 expression in the liver effectively inhibits the sustained hepatic inflammation and cardiovascular damage. Mechanistical studies reveal that high salt increases acetylated histone 3 lysine 27 (H3K27ac) on SIRT3 promoter in hepatocytes, thus inhibiting the binding of NRF2, and results in the sustained inhibition of SIRT3 expression. Treatment with metformin activated AMPK, which inhibited salt-induced hepatic inflammatory memory and cardiovascular damage by lowering the H3K27ac level on SIRT3 promoter, and increased NRF2 binding ability to activate SIRT3 expression. Conclusions: This study demonstrates that SIRT3 inhibition caused by histone modification is the key factor for the persistent hepatic steatosis and inflammation that contributes to cardiovascular damage under high salt loading. Avoidance of excessive salt intake and active intervention of epigenetic modification may help to stave off the persistent inflammatory status that underlies high-salt–induced cardiovascular damage in clinical practice.

The Association of Salt Intake and Non-alcoholic Fatty Liver Disease in People With Type 2 Diabetes: A Cross-Sectional Study

“…In a previous study, high salt intake led to an increase in the sodium levels in liver tissue whereas it was accompanied by a decline in mitochondrial respiratory activity (38). Mitochondrial dysfunction enhances hepatocyte steatosis (38). Moreover, recent experimental studies have shown that high salt intake induces leptin resistance via activating the aldose reductase-fructokinase pathway, production of endogenous fructose and increased white adipose tissue mass via leptin production and adipocyte hypertrophy in the liver (14,35,39).…”

“…Additionally, animal studies have revealed that high salt diet decreases the liver's antioxidant defenses (36) and may promote inflammation and fibrosis in liver (37). In a previous study, high salt intake led to an increase in the sodium levels in liver tissue whereas it was accompanied by a decline in mitochondrial respiratory activity (38). Mitochondrial dysfunction enhances hepatocyte steatosis (38).…”

Potential role of inflammation in relation to dietary sodium and β-carotene with non-alcoholic fatty liver disease: a mediation analysis

“…Results from a recent study showed that mice fed with a high-salt diet displayed obvious hepatic steatosis and inflammation. All these pathological changes persisted after salt withdrawal, displaying a memory phenomenon [38]. In human studies, high sodium intake was reported to be associated with changes in inflammatory markers including tumor necrosis factor-α (TNF-α) and adiponectin [39][40][41].…”

High salt intake damages myocardial viability and induces cardiac remodeling via chronic inflammation in the elderly

“…Salt is necessary for the maintenance of normal physiological reactions in the body and evidence has shown that the average daily salt consumption is >10 g in most populations, which is double the recommendation by the World Health Organization (WHO) of 5 g/day, with the target for many countries being 6 g/day ( 1 , 2 ). High salt intake is believed to lead to a significant increase in the damage to numerous organs such as the heart, blood vessels, kidneys, and brain ( 1 – 4 ) and an association between high salt intake and heart failure has been established ( 5 – 7 ). High salt intake can cause a sustained increase in the left ventricular load, which results in functional and structural changes in the left ventricle ( 8 , 9 ).…”