Pharmacological modulation of cholesterol 7α-hydroxylase (CYP7A1) as a therapeutic strategy for hypercholesterolemia

被引:22
作者
Lim, Megan Yu Cai [1 ]
Ho, Han Kiat [1 ]
机构
[1] Natl Univ Singapore, Fac Sci, Dept Pharm, 18 Sci Dr 4, Singapore 117543, Singapore
关键词
FARNESOID X RECEPTOR; NEGATIVE FEEDBACK-REGULATION; BILE-ACID SYNTHESIS; HMG-COA REDUCTASE; LOWERING RESPONSE; LIVER; FXR; EXPRESSION; METABOLISM; FGFR4;
D O I
10.1016/j.bcp.2023.115985
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Despite the availability of many therapeutic options, the prevalence of hypercholesterolemia remains high. There exists a significant unmet medical need for novel drugs and/or treatment combinations to effectively combat hypercholesterolemia while minimizing adverse reactions. The modulation of cholesterol 7 alpha-hydroxylase (CYP7A1) expression via perturbation of the farnesoid X receptor (FXR) - dependent pathways, primarily FXR/small heterodimer partner (SHP) and FXR/ fibroblast growth factor (FGF)-19/ fibroblast growth factor receptor (FGFR)-4 pathways, presents as a potential option to lower cholesterol levels. This paper provides a comprehensive review of the important role that CYP7A1 plays in cholesterol homeostasis and how its expression can be exploited to assert differential control of bile acid synthesis and cholesterol metabolism. Additionally, the paper also summarizes the current therapeutic options for hypercholesterolemia, and positions modulators of CYP7A1 expression, namely FGFR4 inhibitors and FXR antagonists, as emerging and distinct pharmacological agents to complement and diversify the treatment regime. Their mechanistic and clinical considerations are also extensively described to interrogate the benefits and risks associated with using FXRmediating agents, either singularly or in combination with recognised agents such as statins to target hypercholesterolemia.
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页数:10
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