Several recent researches showed that hypertension, smoking, obesity, age, dyslipidemia, lack of exercise, gender and diabetes mellitus are common risk factors for cardiovascular disease [33, 34]. A comprehensive understanding of the potential molecular mechanisms involved in the pathogenesis of hyperlipidaemia is helpful for its prevention and treatment. As a novel and practical approach to the identification of hyperlipidaemia susceptibility genes, a microarray analysis using WGCNA may be helpful for the diagnosis of hyperlipidemia . WGCNA could be used to build a scale-free co-expression network of lipids-associated genes by detecting gene-to-gene interactions rather than simply focusing on the differentially expressed genes (DEGs). Co-expressed genes were enriched in different modules by hierarchical average linkage cluster analysis. In the present research, we analyzed the dataset from hyperlipidaemia patients (GSE66676) by using WGCNA analysis identified the royalblue module was significantly associated with TC, TG and Non-HDL. Furthermore, KEGG enrichment analyses of the genes in the royalblue module indicated that the enriched genes in this module might have significant potential biological functions that are closely related to metabolic pathways, steroid biosynthesis, fatty acid metabolism and biosynthesis of unsaturated fatty acids. Two hub genes (SQLE and SCD) were identified in the royalblue module that were detected by MCODE analysis. Moreover, the verification results were highly consistent with the above findings, and we found that the expression of the SQLE gene in patients with HCH and SCD gene in patients with HTG were higher than those in healthy controls, respectively. Therefore, the identified SQLE gene was associated with the onset of HCH and SCD gene was associated with the onset of HTG, and the underlying molecular mechanisms of these genes might be slightly different.
Fatty acids and cholesterol are essential lipids involved in lots of crucial biological processes, however, excessive free fatty acids and free cholesterol are major risk factors for type 2 diabetes and atherosclerosis . Previous studies on intermediate metabolites in cholesterol biosynthesis have showed that squalene epoxidase (SQLE) acts as a crucial regulator downstream HMG-CoA reductase in cholesterol synthesis and the first oxygenation step in cholesterol biosynthesis catalyzed by SQLE . Meanwhile, SQLE is suggested as the second rate-limiting enzyme in cholesterol synthesis [37, 38]. Inhibition of SQLE expression could effectively reduce cholesterol synthesis [39, 40] and the cholesterol-lowering effect is caused by the combination of multiple levels. First, SQLE acts as a direct target of SREBP2 transcription factor, plays a crucial regulatory role in most genes in cholesterol biosensors. Second, the N-terminal of SQLE protein may contain a cholesterol-sensitive region that mediates the protease degradation of SQLE in a cholesterol-dependent method through relying on an E3 ubiquitin ligase such as MARCH . Interestingly, oleate acts as one of unsaturated fatty acids can stabilize SQLE by blocking MARCH6-mediated degradation . In addition, Masanori Honsho et al. also noticed that inhibition of SQLE expression through elevating the plasmalogens levels may be a novel and alternative potential method to reduce cholesterol synthesis . Similarly, the KEGG analyses in the current study indicated that SQLE was mainly involved in metabolic pathways and steroid biosynthesis.
Metabolic risk factors such as insulin resistance, obesity, hypertension and dyslipidemia are correlated with each other, so their combination is generally referred to as "metabolic syndrome". Abnormal Stearoyl-coenzyme A desaturase (SCD) expression/activity has been noticed in metabolic syndrome subjects indicating that SCD may be related to the pathogenesis of metabolic syndrome. By querying the GENE database in NCBI, we noticed that SCD (also known as SCD1; FADS5; SCDOS; hSCD1; MSTP008; gene ID: 6319, HGNC: 10571, OMIM: 604031) is positioned on chromosome 10q24.31 (exon count: 6) and encodes a biological synthase, which mainly involved in the metabolism of fatty acids, especially oleic acid, this protein is an intact membrane protein located in the endoplasmic reticulum and is a member of the fatty acid desaturase family. SCD can convert different saturated fatty acids into monounsaturated fatty acids . Both animal and human studies have shown that SCD is associated with obesity and insulin resistance[46, 47]. Mice with the SCD gene destroyed reduced diet-induced weight gain and improved insulin resistance compared to wild-type controls . Deletion of SCD1 gene product in mice could effectively improve insulin sensitivity, reduce plasma non-HDL-cholesterol and triglyceride levels and liver lipid accumulation as well as increase beneficial HDL-cholesterol levels . Daniel Castellano-Castillo et al. also found that a negative relationship between SCD DNA methylation and BMI and the MetS index . In the current study, we also noticed that SCD was mainly involved in fatty acid metabolism and biosynthesis of unsaturated fatty acids pathways.
Unhealthy lifestyle factors such as excessive drinking and cigarette smoking have been linked to hyperlipidaemia [51, 52]. In the present study, we found that the percentage of the participants who smoked was greater in the hyperlipidaemic group than in the normal group. In recent years, the influence of smoking on hyperlipidaemia has attracted increasing attention. Several recent studies have indicated the existence of lower HDL-C and higher TC, LDL-C and TG levels in smokers compared to non-smokers . Moderate drinking reduced the incidence of cardiovascular events, the potential mechanism may be related to increased HDL-C and ApoA1 levels . However, frequent binge drinking was correlated with an increased risk of CAD mortality because it will lead to a number of serious health problems including dyslipidaemia, abnormal liver function and myocardial infarction . Therefore, the preventive effect of healthy lifestyle on hyperlipidemia should not be ignored when exploring new therapeutic targets for hyperlipidemia