Table 2. Effects of Thyroid Hormone, Thyroid Hormone Analogues, and Thyroid Hormone Metabolites in Animal Models of Nonalcoholic Fatty Liver Disease and Hypercholesterolemia on Serum Lipids, Steatosis, Liver Function, Body Weight, Hypothalamic/Pituitary/Thyroid Axis, and Other Side Effects.
| Compound | Study | Animal model (dose) | Serum lipids | Steatosis | Liver function | BW | HPT axis | Other side effects |
|---|---|---|---|---|---|---|---|---|
| TH | ||||||||
| T3 | Grover et al. (141) | Sprague-Dawley rats HCD (1 week, 1.54–154 nmol/kg/day by gavage) | TC ↓ TAG = (ED50 20.6) | TSH ↓ (ED30 9.8) | Heart rate ↑ (ED15 30.8) | |||
| Johansson et al. (70) | C57BL6 mice HCD (8 days, 97 nmol/kg/day intraperitoneal) | TC ↓ TAG ↑ | Liver TAG ↑ | |||||
| Perra et al. (128) | Fischer rats MCD diet (1 week, 6 μmol/kg/diet) | TG ↓ | Liver TAG ↓ | AST, ALT ↓ | BW ↓ | |||
| Cable et al. (135) | ob/ob Mice (9 weeks, 100 nmol/kg/day subcutaneous) | TC ↓ TAG ↑ | Liver TAG = | AST, ALT ↓ | BW ↓ | Heart weight ↑ | ||
| Kannisto et al. (160) | C57BL/6 ApoE-knockout mice HFD (1–10 weeks, 184 nmol/kg/diet) | TC ↓ TAG = | ||||||
| Jonas et al. (146) | C57BL6 mice HFD (4 weeks, 46 nmol/kg/day intraperitoneal) | TC ↓ TAG = | BW = | T4 ↓ T3 = rT3 ↓ T2 = | ||||
| Finan et al. (130) | C57BL6j mice HFHCD (2 weeks, 100 nmol/kg/day subcutaneous) | TC ↓ TAG = | BW = | T4 ↓ T3 ↑ TSH = | Heart rate ↑ heart weight ↑ | |||
| Iannucci et al. (55) | Wistar rats HFD (1 week, 38 nmol/kg/day intraperitoneal) | Liver TAG ↓ | BW = | T4 = T3 ↑ | ||||
| Glucagon-T3 conjugate | Finan et al. (130) | C57BL6j mice HFHCD (2 weeks, 100 nmol/kg/day subcutaneous) | TC ↓ TAG ↓ | BW ↓ | T4 ↓ T3 = TSH = | Heart volume = bone volume = | ||
| C57BL6j mice CD-HFD (3 weeks, 100 nmol/kg/day subcutaneous) | TC ↓ TAG = | Liver TAG ↓ | ALT ↓ | BW ↓ | ||||
| THRβ receptor agonist | ||||||||
| GC-1 (sobetirome) | Grover et al. (141) | Sprague-Dawley rats HCD (1 week, 46.2–27,700 nmol/kg/day by gavage) | TC ↓ TAG = (ED50 190) | TSH ↓ (ED30 190) | Heart rate ↑ (ED15 5451) | |||
| Johansson et al. (70) | C57BL6 mice HCD (8 days, 97 nmol/kg/day intraperitoneal) | TC ↓ TAG = | Liver TAG = | |||||
| Perra et al. (128) | Fischer rats MCD diet (2 weeks, 15 μmol/kg/diet) | TAG ↓ | Liver TAG ↓ | ALT, AST ↓ | BW ↓ | |||
| Vatner et al. (133) | Sprague-Dawley rats HFD (10 days, 499 nmol/kg/day intraperitoneal) | Liver TAG ↓ | BW = | T4 ↓ TSH ↓ | ||||
| Martagon et al. (134) | ob/ob Mice (24 days, 1 μmol/kg/diet) | Liver TAG ↓ | BW ↓ | |||||
| KB2115 (eprotirome) | Vatner et al. (133) | Sprague-Dawley rats HFD (10 days, 205 nmol/kg/day intraperitoneal) | Liver TAG ↓ | BW = | T4 ↓ TSH ↓ | |||
| Martagon et al. (134) | ob/ob Mice (24 days, 6 μ/kg/diet) | Liver TAG ↓ | BW ↓ | |||||
| Prodrug THRβ receptor agonist | ||||||||
| MB07811 (prodrug MB07344) | Erion et al. (139) | C57BL/6 mice HFD (2 weeks, 6 μmol/kg/day) | TC ↓ TAG ↓ | Liver TAG ↓ | BW = | T4 ↓ T3 ↓ | Heart weight = | |
| Cable et al. (135) | Zucker diabetic fatty rats (28 days, 2–97 μmol/kg/day by gavage) | TC ↓ TAG = | Liver TAG ↓ | ALT/AST = | BW = | Heart rate = | ||
| C57BL6 mice HFD (2 weeks, 6–60 μmol/kg/day by gavage) | TC ↓ TAG = | Liver TAG ↓ | ALT/AST = | BW = | Heart rate, heart weight = | |||
| ob/ob Mice (9 weeks, 19–58 μmol/kg/day by gavage) | TC ↓ TAG = | Liver TAG ↓ | AST, ALT ↓ | BW ↓ | Heart weight = | |||
| Ito et al. (164) | Rabbits HCD (5 weeks, 19 μmol/kg orally in diet) | TC ↓ | ||||||
| TH metabolite | ||||||||
| T2 | Mollica et al. (145) | Wistar rats HFD (4 weeks, 476 nmol/kg/day intraperitoneal) | TC ↓ TAG ↓ | Liver TAG ↓ | ALT ↓ | BW ↓ | TSH = | |
| Goldberg et al. (64) | C57BL6 mice WD (1 week, 2–20 μmol/kg/day by gavage) | TC ↓ TAG ↑ | BW = | T4 ↓ | ||||
| Jonas et al. (146) | C57BL6 mice HFD (4 weeks, 4761 nmol/kg/day) | TC ↓ TAG = | Liver TAG ↓ | BW = | T4 ↓a T3 ↓a rT3 ↓ T2 ↑a | Heart weight ↑ | ||
| Iannucci et al. (55) | Wistar rats HFD (1 week, 476 nmol/kg/day intraperitoneal) | Liver TAG ↓ | BW = | T4 = T3 = | ||||
| T1AM | Assadi-Porter et al. (90) | CD-1 mice (1 week, 70 μmol/kg/day) | TC ↓ TAG ↑ | BW ↓ | ||||
| TRC150094 (T2 mimetic) | Zambad et al. (150) | Obese ZSF1 rats (24 weeks, 18–37 μmol/kg/day orally) | TC = TAG = | Liver fat (MRS) ↓ | Bilirubin ↓ | BW ↓/ = | Heart rate =, cardiac output = | |
| Silvestri et al. (149) | Wister rats HFD (4 weeks, 23 μmol/kg/day intraperitoneal) | TC = TAG = | BW = | fT4 = fT3 = TSH = | Heart weight = | |||
| Triac | Cable et al. (135) | Sprague-Dawley rats normal chow diet (7 days, 1 μmol/kg/day via minipump) | Liver TAG ↓ | BW = | Heart weight ↑ | |||
EDn: dose in nmol/kg/day causing an n % change.
a
Also significantly changed in 476 nmol/kg/day.
ALT, alanine transaminase; AST, aspartate transaminase; BW, body weight; CD-HFD, choline-deficient high-fat diet; fT3, free triiodothyronine; fT4, free thyroxine; HCD, high-cholesterol diet; HFD, high-fat diet; HFHCD; high-fat high-cholesterol diet; HPT, hypothalamic/pituitary/thyroid; MCD, methionine- and choline-deficient; T4, thyroxine; TC, total cholesterol; TAG, triglycerides; TSH, thyrotropin; WD, western diet.