Lanosterol is a triterpenoid intermediate in the biosynthesis of cholesterol, which can induce the ubiquitination and degradation of HMG CoA reductase [1]. Defects in Lanosterol can lead to various diseases, including the formation of cataracts [2]. Lanosterol can inhibit the aggregation and toxicity of misfolded proteins related to neurodegenerative diseases [3].
In vitro, treatment with Lanosterol (5μM; 24h) significantly inhibited the cell death of dopaminergic neurons induced by 1-methyl-4-phenylpyridine (MPP+), increased autophagy in neurons, and induced uncoupling of mitochondria in neurons [4]. Treatment with Lanosterol (20μM; 48h) increased the endogenous level of 20S proteasome in A549 and Cos-7 cell lines, promoted proteasome degradation of misfolded proteins, and reduced the aggregation of mutant GFP-Δ9CAT protein [5].
In vivo, oral administration of Lanosterol (1 or 2%, w/w; 10 weeks) significantly inhibited the formation of abnormal crypts and multiple crypts in rat colon induced by nitrosomethane (AOM), and 2% Lanosterol significantly increased serum high-density lipoprotein and cholesterol levels [6]. Local ocular administration of Lanosterol (25mM; 6 weeks) improved the clarity of canine lenses and alleviated cataracts [7].
References:
[1] Chen N, et al. Biosynthetic Mechanism of Lanosterol: Cyclization. Angew Chem Int Ed Engl. 2015 Jul 20;54(30):8693-6.
[2] Zhao L, Chen X J, Zhu J, et al. Lanosterol reverses protein aggregation in cataracts[J]. Nature, 2015, 523(7562): 607-611.
[3] Upadhyay A, Amanullah A, Mishra R, et al. Lanosterol suppresses the aggregation and cytotoxicity of misfolded proteins linked with neurodegenerative diseases[J]. Molecular neurobiology, 2018, 55(2): 1169-1182.
[4] Lim L, Jackson-Lewis V, Wong L C, et al. Lanosterol induces mitochondrial uncoupling and protects dopaminergic neurons from cell death in a model for Parkinson's disease[J]. Cell Death & Differentiation, 2012, 19(3): 416-427.
[5] Kinger S, Jagtap Y A, Dubey A R, et al. Lanosterol elevates cytoprotective response through induced-proteasomal degradation of aberrant proteins[J]. Biochimica et Biophysica Acta (BBA)-Molecular Cell Research, 2024, 1871(2): 119631.
[6] Rao C V, Newmark H L, Reddy B S. Chemopreventive effect of farnesol and lanosterol on colon carcinogenesis[J]. Cancer detection and prevention, 2002, 26(6): 419-425.
[7] Zhao L, Chen X J, Zhu J, et al. Lanosterol reverses protein aggregation in cataracts[J]. Nature, 2015, 523(7562): 607-611.
Lanosterol是胆固醇生物合成过程中的一种三萜类中间体，能够诱导HMG CoA还原酶的泛素化和降解 [1]。Lanosterol的缺陷会导致多种疾病，其中包括白内障的形成 [2]。Lanosterol能够抑制与神经退行性疾病相关的错误折叠蛋白质的聚集和毒性作用 [3]。
在体外，Lanosterol（5μM; 24h）处理显著抑制了1-甲基-4-苯基吡啶（MPP+）诱导的多巴胺能神经元的细胞死亡，增加了神经元的自噬并诱导神经元中线粒体的解偶联 [4]。Lanosterol（20μM; 48h）处理增加了A549和Cos-7细胞系中20S蛋白酶体的内源性水平，促进错误折叠蛋白质的蛋白酶体降解，并减少了突变型GFP-Δ9CAT蛋白的聚集 [5]。
在体内，Lanosterol（1 or 2%, w/w; 10 weeks）通过口服治疗显著抑制了氮氧甲烷（AOM）诱导的大鼠结肠异常隐窝病灶（ACF）以及多隐窝病灶的形成，2%的Lanosterol显著增加了血清高密度脂蛋白和胆固醇水平 [6]。Lanosterol（25mM; 6 weeks）通过眼局部给药治疗提高了犬类晶状体的清晰度，缓解已形成的白内障 [7]。