Cholesterol Absorption and Synthesis Markers: Risk for Cardiovascular Diseases?

See article vol. 30: 1766-1777

Serum cholesterol levels, particularly total cholesterol and low-density lipoprotein (LDL) cholesterol have long been known to be strongly associated with the risk of developing cardiovascular disease (CVD). The cholesterol pathway is an important target not only for CVD prevention but also for individual CVD risk stratification. In addition to classical serum lipid levels, there have been many recent reports on the association of novel lipid-related markers such as postprandial hypertriglyceridemia ¹⁾ , high-density lipoprotein (HDL) cholesterol efflux capacity ^{2 , 3)} , and eicosapentaenoic acid (EPA): arachidonic acid (AA) ratio ⁴⁾ with the risk of developing CVD.

Cholesterol absorption and synthesis are among these novel biomarkers, and several epidemiologic studies have been conducted to determine whether they are independent cardiovascular risk factors. For example, in a nested case-control study of participants in the Framingham Offspring Study ⁵⁾ , those with preexisting CVD or carotid artery stenosis had significantly higher levels of cholesterol absorption markers than controls, while cholesterol synthesis markers were significantly lower. Even after adjustment for classic cardiovascular risk factors, a cholesterol absorption marker campesterol (2.47 [1.71-3.56]), or a cholesterol synthesis marker lathosterol (0.58 [0.43-0.77]) were significantly associated with CVD (odds ratio [95% confidence interval]).

Here, Katsuki et al. reported the results of the CACHE (Cholesterol Absorption and Cholesterol synthesis in High-risk patiEnts) study ⁶⁾ . This is the first, nationwide multicenter cross-sectional study, showed a significant correlation between cholesterol absorption markers and cholesterol synthesis markers and the risk of CVD in Japanese subjects. They analyzed data from 2,895 people and clearly demonstrated that positive association between serum levels of campesterol and CVD, and inverse association between those of lathosterol and CVD. Cholesterol absorption and synthesis are strongly influenced by lipid-lowering drugs such as statins and ezetimibe. In this regard, the CACHE study is significant because it demonstrates an association between serum campesterol and lathosterol concentrations and CVD, even when patients taking these drugs are excluded.

Recently, Yoshida et al. reported the serum levels of campesterol and lathosterol in healthy Japanese subject ⁷⁾ . They measured the non-cholesterol sterol by highly sensitive gas chromatography (GC) method and showed the gender difference: the serum levels of campesterol are significantly higher in women than in men, while those of lathosterol are significantly higher in men than in women. The mean serum campesterol levels were 4.20±1.46 µg/mL for men and 4.53±1.59 µg/mL for women. In contrast, mean serum lathosterol levels were 1.80±0.72 µg/mL for men and 1.42±0.52 µg/mL for women.

The CACHE study included a large number of patients at high risk of CVD. In this study, the laboratory analysis for campesterol and lathosterol measurements were performed by the similar GC method, and the median serum concentrations of campesterol and lathosterol were 4.70 µg/mL and 1.90 µg/mL, respectively. It is possible that the slightly higher serum concentrations of campesterol in the CACHE study compared with those in healthy subjects may reflect the older age or susceptibility to CVD of the enrolled patients; however, each serum concentration value is within normal range ⁷⁾ .

The CACHE study is very significant as the first large-scale Japanese clinical study to demonstrate an association between the cholesterol absorption marker campesterol and the synthetic marker lathosterol and CVD, but the study has some limitations and the results should be interpreted with caution.

First, as noted above, Yoshida et al. reported gender differences in serum campesterol and lathosterol concentrations, but the CACHE study has no information on gender differences in outcomes. More importantly, because of the cross-sectional design of the study, a causal relationship between serum campesterol or lathosterol concentrations and the occurrence of CVD cannot be determined from the results of the CACHE study. Appropriately designed cohort studies are needed to prove that these serum non-cholesterol sterol levels are true cardiovascular risk factors in the Japanese population, which has a lower risk of cardiovascular events compared with Western populations.

It has long been reported that cholesterol absorption is increased in patients at high risk for cardiovascular events, such as those with metabolic syndrome and type 2 diabetes, but the mechanism is not fully understood ⁸⁾ . Although many complex and sophisticated regulatory mechanisms at the genetic, transcriptional and protein levels have been reported, much remains to be understood about the molecular networks involved in cholesterol synthesis and absorption and how dysfunction of each mechanism leads to the development of cerebrovascular and cardiovascular outcomes. The significance of biomarkers, including serum campesterol and lathosterol concentrations, by outcome, comorbidity, age group, and gender should be evaluated in appropriate clinical research to provide clues to elucidate the mechanisms of CVD, and eventually contribute to the realization of personalized medicine in the management of dyslipidemia in Japanese patients.

Conflict of Interest

None.