Table 3 iMAT-based metabolic network modeling of cholesterol synthesis and catabolism in AD.

From: Abnormal brain cholesterol homeostasis in Alzheimer’s disease—a targeted metabolomic and transcriptomic study

   

ERC

Hippocampus

Visual cortex

Gene

Human GEM rxn ID

GEM reaction

Odds ratio

P value

Odds ratio

P value

Odds ratio

P value

De novo cholesterol biosynthesis (pre-squalene mevalonate pathway)

ACAT2

HMR_1434

acetoacetyl-CoA[c] + CoA[c] <=> 2 acetyl-CoA[c]

1.500

1.000

0.070

0.006

0.000

0.510

HMGCS1

HMR_1437

acetoacetyl-CoA[c] + acetyl-CoA[c] + H2O[c] => CoA[c] + H+[c] + HMG-CoA[c]

0.721

0.603

0.178

0.028

1.018

1.000

HMGCR

HMR_1440

2 H+[c] + HMG-CoA[c] + 2 NADPH[c] => (R)-mevalonate[c] + CoA[c] + 2 NADP+[c]

0.522

0.322

0.087

0.016

0.000

0.265

De novo cholesterol biosynthesis (post-squalene mevalonate pathway including Bloch and Kandutch-Russell)

SC5D

7DHCHSTEROLtr

7-dehydrocholesterol[r] <=> 7-dehydrocholesterol[c]

0.353

0.049

0.518

0.204

1.786

0.676

DHCR7

HMR_1565

H+[c] + NADPH[c] + 7-dehydrocholesterol[c] => cholesterol[c] + NADP+[c]

0.248

0.009

0.308

0.097

3.929

0.363

DHCR7

DHCR72r

H+[r] + NADPH[r] + 7-dehydrocholesterol[r] => cholesterol[r] + NADP+[r]

0.308

0.023

0.171

0.008

1.786

0.676

SC4MOL, SC5D

C14STRr

H+[r] + NADPH[r] + 4,4-dimethyl-5alpha-cholesta-8,14,24-trien-3-beta-ol[r] => NADP+[r] + 14-demethyllanosterol[r]

0.144

0.001

0.121

0.000

0.134

0.021

SC4MOL

C4STMO2Pr

NADP+[r] + O2[r] + 3-keto-4-methylzymosterol[r] => CO2[r] + H+[r] + NADPH[r] + zymosterol Intermediate 2[r]

0.750

1.000

0.000

0.047

NA

1.000

SC5D

HMR_1516

5alpha-cholesta-7,24-dien-3-beta-ol[c] + H+[c] + NADPH[c] + O2[c] => 7-dehydrodesmosterol[c] + 2 H2O[c] + NADP+[c]

0.188

0.002

0.186

0.006

Inf

0.265

SC5D

LSTO1r

H+ [r] + NADPH[r] + O2[r] + 5alpha-cholesta-7,24-dien-3-beta-ol[r] => 2 H2O[r] + NADP+[r] + 7-dehydrodesmosterol[r]

0.000

0.031

NA

1.000

0.000

0.510

DHCR7

HMR_1519

7-dehydrodesmosterol[c] + H+[c] + NADPH[c] => desmosterol[c] + NADP+[c]

0.188

0.002

0.186

0.006

Inf

0.265

DHCR7

DHCR71r

H+[r] + NADPH[r] + 7-dehydrodesmosterol[r] => NADP+ [r] + desmosterol[r]

0.000

0.031

NA

1.000

0.000

0.510

DHCR24

HMR_1526

desmosterol[c] + H+[c] + NADPH[c] => cholesterol[c] + NADP+[c]

0.103

0.036

0.000

0.341

0.000

0.510

DHCR24

DSREDUCr

H+[r] + NADPH[r] + desmosterol[r] => cholesterol[r] + NADP+[r]

0.103

0.036

0.000

0.341

0.000

0.510

DHCR24

DSMSTEROLtr

desmosterol[r] => desmosterol[c]

1.083

1.000

2.824

0.035

0.000

0.139

Cholesterol catabolism (enzymatic)

HSD3B7

HMR_1738

cholest-5-ene-3-beta,7alpha,24(S)-triol[c] + NAD+[c] => 4-cholesten-7alpha,24(S)-diol-3-one[c] + H+[c] + NADH[c]

4.164

0.021

2.724

0.116

2.400

0.288

  1. GEM genome-scale metabolic model, Human-GEM rxn ID Human GEM reaction ID is searchable in metabolicatlas.org and indicates the specific reaction equation and additional reaction details, AD Alzheimer’s disease, CN control, ERC entorhinal cortex, [c] cytoplasm, [m] mitochondria, [r] endoplasmic reticulum; P < 0.05 in bold.
  2. Significant (P < 0.05) odds ratios <1.0 indicate that the reaction is less active in AD compared to CN; significant odds ratios >1.0 indicate that the reaction is more active in AD compared to CN. Note that all significant de novo cholesterol biosynthesis reactions other than DSMSTEROLtr are less active in AD compared to CN. “Inf” indicates that one of the values for calculating the odds ratio (either the number of AD or CN samples that were either active or inactive for a particular reaction) was 0. “NA” indicates two of the values for calculating the odds ratio (the number of AD and CN samples that were either active or inactive for a particular reaction) was 0. Significant associations (P < 0.05) are indicated in bold. Gene Expression Ominbus (GEO) data sample size: ERC: AD (n = 25), CN (n = 52); hippocampus: AD (n = 29), CN (n = 56); visual cortex: AD (n = 18), CN (n = 12).
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