Exquisite Balance Between Cholesterol Synthesis and Cholesterol Absorption in Human

See article vol. 30: 1152-1164

Cholesterol Homeostasis and Accurate Diagnosis

It is well known that serum cholesterol is an important substance not only for humans but also for other animals. Cholesterol is an important structural component of animal cell membranes, and it also serves as a precursor for the biosynthesis of steroid hormones, bile acid and fat-soluble vitamins¹⁾. Therefore, cholesterol homeostasis is strictly regulated via biosynthesis and absorption (Fig.1). The imbalance of cholesterol homeostasis can be caused by different situations, including genetic causes, such as familial hypercholesterolemia (FH) where serum cholesterol level increases too much²⁾, while there are other situations such as abetalipoproteinemia where serum cholesterol level is too low³⁾. In the cases of FH, where there is a loss of function mutation in LDL receptor (LDLR) impairs the uptake of LDL particles into liver, increase of synthesis of cholesterol has been shown as the cause of their elevation in LDL cholesterol level via kinetic studies in vivo⁴⁾. Alternatively, sitosterolemia, which is caused by the biallelic loss of function mutations in ATP-binding cassette subfamily G member 5 (ABCG5) or ATP-binding cassette subfamily G member 8 (ABCG8) exhibits the elevation of LDL cholesterol because of the increase of the absorption of sterols⁵⁾. Based on these facts, statins are quite effective to reduce LDL cholesterol among patients with FH, whereas ezetimibe is effective among patients with sitosterolemia in general. In this study, Matsuki. et al. showed that the absorption of cholesterol is also increased among patients with FH, which should be a bad combination from the viewpoint of preventive cardiology⁶⁾. There are several potential reasons for this situation. First, cholesterol homeostasis via its synthesis and absorption are independently working. However, it has been shown that statins can increase cholesterol absorption as a result of the inhibition of cholesterol synthesis⁷⁾. So, we do not think it is a major cause of this situation. Second, increased cholesterol absorption is contributing to lead the patients to the point as “FH.” In this regard, we have shown that at least a portion of patients with FH are actually the sitosterolemia or carriers of ABCG5 or ABCG8 ⁸⁾. Although the effect size on LDL cholesterol via mutations in ABCG5 or ABCG8 is much smaller than that by LDLR or proprotein convertase subtilisin/kexin type 9 (PCSK9), ABCG5 and ABCG8 are likely to contribute to mimic the phenotype of FH. For such patients, ezetimibe has been shown to be quite effective to reduce their LDL cholesterol⁹⁾. Accordingly, “accurate” diagnosis is likely to be beneficial in terms of precision medicine¹⁰⁾.

Fig.1.

Cholesterol Homeostasis in Human

Conclusion

We speculate that at least a part of patients with FH are caused by increased cholesterol absorption, rather than increased cholesterol synthesis. Precision medicine can be provided if we care regarding this issue.

Acknowledgements

None.

Conflict of Interest

None.

Sources of Funding

None.

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