This study conducted a comprehensive analysis by systematically integrating all relevant prospective research to further explore the association between blood lipid levels and liver cancer risk. The study covered a large number of participants from multiple countries, ensuring high reliability of the results. The findings revealed that higher levels of total cholesterol (TC), triglycerides (TGs), and high-density lipoprotein cholesterol (HDL-C) were associated with a reduced risk of liver cancer, whereas there was no correlation between serum low-density lipoprotein cholesterol (LDL-C) and liver cancer risk. These study results contribute to clarifying the link between blood lipid levels and liver cancer risk. Moreover, this discovery aids in using blood spectrum analysis to predict liver cancer risk in high-risk populations.
Metabolic alterations are widely recognized as hallmarks of cancer (38), and there is a close association between dyslipidemia and the development of liver cancer (22). Previous research has indicated that elevated levels of total cholesterol (TC) increase the risk of cardiovascular diseases (39–41). However, this current study reveals a paradoxical finding where higher TC levels are actually associated with a reduced risk of liver cancer. This association may be attributed to the diverse functions of TC in different organs within the human body. In the liver, cholesterol is involved in bile acid synthesis, and bile acids have been shown to slow down liver damage and the progression of hepatocellular carcinoma (42, 43). Furthermore, studies suggest that receptor tyrosine kinases (RTKs) play a critical role in tumor malignant transformation and cancer metastasis (44), and cholesterol inhibits RTK autophagic degradation in a GOLM1-dependent manner (45, 46). Similarly, research has demonstrated that estrogen exerts a significant protective effect against hepatocellular carcinoma (47), and as cholesterol serves as a precursor for steroid hormones, epidemiological studies have shown an increased incidence of liver cancer in postmenopausal women (48). Nevertheless, further research is warranted to elucidate these potential mechanisms fully.
Previous studies have indicated an association between TG and various cancers (40), such as an increased risk of colorectal (49), prostate (50), and breast cancer(51) with higher triglyceride levels. This meta-analysis combines the results of 8 prospective cohort studies and demonstrates a significant inverse association between TG and liver cancer. The potential mechanism underlying triglycerides as a protective factor against liver cancer in this study may be linked to the expression level of diacylglycerol acyltransferase (DGAT) (52), as confirmed in previous research. High DGAT2 expression is associated with prolonged overall survival in cancer patients (52, 53), and these findings have been validated in in vitro and in vivo experiments, indicating that DGAT2 overexpression can inhibit cell proliferation and reduce tumor growth (52). DGAT is a key enzyme that facilitates the conversion of diacylglycerol (DAG) to triglycerides (TAG) (54), which is an essential step in fatty acid synthesis and storage. Normal triglyceride metabolism is crucial for maintaining lipid balance in the liver and the whole body. Moreover, some studies have suggested that lower triglyceride levels may be related to excessive fat accumulation and the development of fatty liver in the liver (55). However, this remains a hypothesis, and further research is needed to explore the potential benefits of triglycerides in anti-tumor aspects.
A meta-analysis investigating the association between HDL-C and gastric cancer risk has also reported similar findings (56). In this current study, a link was revealed between higher levels of HDL-C and a reduced risk of liver cancer. However, the specific mechanisms underlying HDL's role in lowering liver cancer risk remain unclear. Firstly, HDL-C may act as a reverse transporter of cholesterol in the body, collecting excess cholesterol and aiding in its clearance (57, 58), thus maintaining cholesterol balance. Secondly, HDL-C also exhibits antioxidant and anti-inflammatory properties, reducing intracellular oxidative stress and inflammation (59, 60), which are closely associated with the occurrence and development of cancer (61). Reports have shown that HBV and HCV are independent risk factors for liver cancer (62, 63), and a case-control study indicated lower levels of cholesterol, triglycerides, and high-density lipoprotein in the serum of HCV patients compared to the control group (64). Although these observed phenomena are intriguing, direct evidence supporting the hypothesized negative correlation between HDL and liver cancer is currently lacking. Therefore, future research should further explore the physiological mechanisms underlying the association between HDL-C and liver cancer to better understand its role in the development of the disease.
In this meta-analysis, no significant association between LDL-C and liver cancer risk was observed. While other studies have suggested that lowering LDL-C levels can enhance the effectiveness of statin therapy for stroke (65) and that elevated LDL-C increases the risk of cardiovascular diseases (66, 67), similar results related to liver cancer were not observed in this study. Additionally, numerous studies have shown that high LDL-C levels are risk factors for various cancers, such as lung (68) and breast cancer (69). However, the lack of association in this study may be attributed to the fact that elevated LDL-C levels are often associated with dyslipidemia (70), and the observed link between LDL-C and cancer risk might be a secondary effect. It is also possible that the impact of LDL-C on cancer risk appears to vary depending on the site of cancer. Furthermore, this study only included two prospective cohort studies, leading to a high level of heterogeneity (I2 = 93%, P < 0.01). In the future, improvements in study design and increased sample size would be beneficial in gaining a deeper understanding of the potential association between LDL-C and liver cancer.
Advantages and limitations
The strength of this meta-analysis lies in its comprehensive inclusion of large-scale, prospective studies with extended follow-up periods, rather than relying on case-control studies, thus reducing potential limitations associated with case-control designs that could affect result accuracy. Additionally, the substantial number of participants and case data ensures the validity and reliability of the findings. Furthermore, the results of sensitivity analyses indicate stability, and no evidence suggests publication bias in any of the included studies. Taken together, these factors contribute to enhancing the reliability of the research findings. Despite conducting numerous subgroup and sensitivity analyses, the statistical significance of the sources of heterogeneity in these variations has not been definitively determined. However, the study results still demonstrate significant heterogeneity, which may impact the overall reliability of the pooled outcomes. This heterogeneity could stem from factors not accounted for in the analysis, such as lifestyle behaviors, individual differences, dietary habits, comorbidities, and psychological factors, which could potentially influence disease incidence rates. Therefore, when interpreting the results, it is crucial to cautiously consider these potential confounding factors and comprehensively assess their potential impact on the study outcomes. Additionally, while we employed explicit inclusion criteria, differences in comparison methods could contribute to heterogeneity. For instance, comparing the highest reading of serum lipid profiles with the lowest group may yield different estimates, as some studies may categorize groups based on quartiles of serum concentrations, while others may use normal ranges as the basis for categorization. As a result, to gain a more accurate understanding of the research findings, it is essential to integrate and fully comprehend the implications of these diverse measurement criteria on the study conclusions.