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