As the largest metabolic organ, the liver plays an important role in the health of the body, including three major nutrients and various molecular metabolic events, and this organ hosts some key nodes. Thus, some abnormalities will have potential impacts on health. We compared the transcriptome changes in the liver of mice fed with high-salt diet by transcriptome sequencing and found that there were many abnormal signal pathways and metabolic events in the liver after exposure to a high-salt diet. For example, two up-regulated genes, cyp4a10 and cyp4a14, were shown to be involved in the PPAR signaling pathway and related to oxidative stress and lipid peroxidation of fatty acids, causing NAFLD/steatohepatitis (NASH). In steroid hormone biosynthesis pathways, the cyp17a1 gene was down-regulated, and in cell proliferation and apoptosis regulation pathways, nr4a1 gene expression was down-regulated. Many of the pathways we identified here have been previously reported. In addition, we also found some other potential effects, such as retinol metabolism, ascorbate and aldarate metabolism, and steroid hormone biosynthesis, which have not been reported previously and can provide mechanistic support for disease prediction of those caused by a high-salt diet.
It has been reported that long term high-salt diet can directly cause liver fibrosis, or lead to liver fat accumulation, suggesting lipoprotein transport disorders are caused by a high-salt diet [16, 27]. In addition, studies have shown that a high-salt intake increases liver osmotic pressure, promotes the expression of the transcription factor TonEBP, and then activates the expression of aldose reductase, promoting the production of endogenous fructose. Therefore, salt may be a potential cause of obesity and metabolic syndrome [15]. Accordingly, a study also found that the prevalence of NAFLD increased with an increase in Na+ intake, implying the effect of a high-salt diet on liver lipid metabolism and the potential relationship between NAFLD and obesity [28]. Although our results showed that after 6 weeks of high-salt diet, biochemical and H༆E staining showed no obvious liver damage (probably due to the short time of high-salt feeding, where organic damage had not yet formed), sequencing results provided clues to the potential influences which need to be further researched.
There is a significant correlation between high salt diet and hypertension. A large amount of evidence has shown that salt is the main cause of blood pressure elevation, and a decrease in salt intake reduces blood pressure, thus reducing the diseases related to blood pressure. The central mechanism of hypertension shows that a high-salt diet leads to an increase of the brain’s sodium ion content, which activates the sympathetic nerves through the Na(+)-ENaC-RAAS-EDLF axis and promotes the formation of hypertension [29]. It has also been found that salt may induce salt-sensitive hypertension by inhibiting the expression of renal enzymes [30]. In addition, high sodium levels can directly promote the proliferation of vascular smooth muscle cells and promote the formation of hypertension [31]. Our results also showed that the expression of the cyp4a gene in the liver was significantly increased, while Cyp4a protein could hydroxylate arachidonic acid into 20-hydroxyeicosapentaenoic acid and act on blood vessels, which indirectly participate in the formation of hypertension. This finding also supported a previous mechanism of a high-salt diet leading to hypertension [32].
With the continuous development and popularization of omics research technology (including proteome, transcriptome, and metabolomic) over the past few years, people have gained the ability to systematically describe and analyze the changes of specific levels of the body as a whole, so as to further explore the pathogenesis of diseases, allowing them to identify the potential pathogenic risks and influencing factors for these diseases. Among these technologies, transcriptome sequencing technology is an important means to study the pathogenesis of many diseases. Since transcription levels are often positively correlated with protein expression levels, transcriptome sequencing can be used to analyze and predict the occurrence and development of diseases. By comparing and analyzing the differential genes under different conditions in the transcriptional phase, we can identify changes that may be related to diseases. We also could analyze the correlation between various pathways, thus providing clues to the pathogenesis of diseases. This study systematically analyzed the liver after high-salt diet at the transcriptomics level, and we found many potential risks for diseases, which provide clues to the pathogenesis, prevention, and drug target research of diseases. These potential pathogenic factors will be further explored in the future.