Increased Plasma Level of 24S-Hydroxycholesterol and Polymorphism of CYP46A1 SNP (rs754203) Are Associated With Mild Cognitive Impairment in Patients With Type 2 Diabetes

Abstract

BackgroundAbnormal cholesterol metabolism is common in type 2 diabetes mellitus (T2DM) and causes dementia. Cholesterol 24S-hydroxylase (CYP46A1) converts cholesterol into 24S-hydroxycholesterol (24-OHC) and maintains cholesterol homeostasis in the brain.ObjectiveThis study aimed to investigate the roles of 24-OHC and the CYP46A1 (rs754203) polymorphism in patients with T2DM and mild cognitive impairment (MCI).MethodsA total of 193 Chinese patients with T2DM were recruited into two groups according to the Montreal Cognitive Assessment (MoCA). Demographic and clinical data were collected, and neuropsychological tests were conducted. Enzyme-linked immunosorbent assay (ELISA) and Seqnome method were used to detect the concentration of plasma 24-OHC and the CYP46A1 rs754203 genotype, respectively.ResultsCompared with 118 healthy cognition participants, patients with MCI (n = 75) displayed a higher plasma level of 24-OHC and total cholesterol concentration (all p = 0.031), while no correlation was found between them. In the overall diabetes population, the plasma level of 24-OHC was negatively correlated with MoCA (r = −0.150, p = 0.039), and it was further proved to be an independent risk factor of diabetic MCI (OR = 1.848, p = 0.001). Additionally, patients with MCI and the CC genotype of CYP46A1 rs754203 showed the highest plasma level of 24-OHC even though the difference was not statistically significant, and they obtained low scores in both the verbal fluency test and Stroop color and word test A (p = 0.008 and p = 0.029, respectively).ConclusionIn patients with T2DM, high plasma level of 24-OHC and the CC genotype carrier of CYP46A1 rs754203 may portend a high risk of developing early cognitive impairment, including attention and executive deficits.

Molecular basis for the recognition of 24-(S)-hydroxycholesterol by integrin αvβ3

“…For example, age-related macular degeneration (AMD) results in elevated levels of circulatory 24HC [28][29][30]34 . Moreover, several neurological and metabolic conditions (e.g., Alzheimer's, glaucoma, obesity) affect plasma 24HC concentration [23][24][25][26][28][29][30]34 . Thus, 24HC levels in circulation during various pathophysiological conditions may regulate cellular immune homeostasis.…”

“…24HC is also called cerebrosterol since it plays an important role in maintaining cholesterol homeostasis in the brain 22 . It has also been implicated in several diseases, including Alzheimer's, glaucoma, and obesity [22][23][24][25][26] . The conversion of the blood-brain barrier impermeable cholesterol to highly permeable 24HC and transport to the peripheral/ systemic circulation is regarded as a major mechanism of cholesterol removal from the brain to maintain cholesterol homeostasis [26][27][28][29][30] .…”

Identification of differentially expressed genes and signaling pathways in gestational diabetes mellitus by integrated bioinformatics analysis

“…Pathways include hemostasis [57], neutrophil degranulation [58], immune system [59] and cytokine signaling in immune system [60] are responsible for progression of GDM. LGR5 [61], GREM1 [62], GLRA3 [63], NEUROD4 [64], CYP2J2 [65], KCNH6 [66], LBP (lipopolysaccharide binding protein) [67], CXCL14 [68], RGN (regucalcin) [69], NPY2R [70], SERPINB13 [71], WNT5A [72], EDA (ectodysplasin A) [73], HSD11B2 [74], ACVR1C [75], NEUROD1 [76], SLIT2 [77], PPARGC1A [78], IGF1 [79], OSR1 [80], CYP46A1 [81], TLR3 [82], BMP7 [83], SELP (selectin P) [84], HLA-A [85], NOTCH2 [86], LRP1 [87], CLU (clusterin) [88], FCN1 [89], CDKN1A [90], SMAD3 [91], HLA-E [92], PTPRC (protein tyrosine phosphatase receptor type C) [93], MYH9 [94], JAK3 [95], IL6R [96], TIMP1 [97], DOCK8 [98], TNFRSF1B [99], ITGAL (integrin subunit alpha L) [100], CD47 [101], RARA (retinoic acid receptor alpha) [102], DGKD (diacylglycerol kinase delta) [103], PLEK (pleckstrin) [104], PREX1 [105], BSCL2 [106], PANX1 [107], IRF7 [108], NOTCH1 [109], STIM1 [110], TRIM13 [111], LRBA (LPS responsive beige-like anchor protein) [112], CXCR4 [113], MDM4 [114], MYO9B [115] and PDE5A [116] were revealed to be expressed in diabetes mellitus, but these genes might be novel targets for GDM. SIX1 [117], GREM1 [118], GHRHR (growth hormone releasing hormone receptor) [119], GPR37L1 [120], CYP2J2 [121], AQP4 [122], ROS1 [123], LBP (lipopolysaccharide binding protein) [124], SGCD (sarcoglycan delta) [125], CXCL14 [126], RGN...…”

The Interaction Effect of 27‐Hydroxycholesterol Metabolism Disorder and CYP27A1 Single Nucleotide Polymorphisms in Mild Cognitive Impairment: Evidence from a Case–Control Study

“…[ 19 ] Recent study in China has shown that high level of plasma 24S‐hydroxycholesterol (24S‐OHC) and C‐carrier genotype of CYP46A1, 24‐hydroxylase (CYP26A1) polymorphism rs754203 was related to high risk reduction in attention and executive function, was converted from cholesterol mediated by CYP46A1. [ 20 ] 24S‐OHC is the pathway of cholesterol elimination from the brain in addition to 27‐OHC, the balance of 27‐OHC and 24S‐OHC is essential for AD development. [ 21 ] Various studies have reported the polymorphism of cholesterol related gene was essential for AD, however, no research concerned about CYP27A1 polymorphism and the interaction effect with 27‐OHC.…”