Table 1.
Summary of loss-of-function mouse models revealing liver-specific corepressor functions and target TFs.
| Protein name (gene name) | Mouse model | Key features of the phenotype | Target TF | References |
|---|---|---|---|---|
| NCOR (Ncor1) | Global KO | • Embryonic lethality at E15.5 • Impaired erythroid, thymocyte, and CNS development |
– | (17) |
| Liver NCORi transgenic | • Overexpression of a dominant-negative NCOR blocked basal transcription of TR-responsive genes but had no effect on ligand-activation • Increased endogenous SMRT and NCOR mRNA expression • Increased hepatocyte proliferation in euthyroid mice |
TR | (18) | |
| Liver NCOR ΔRID knockin |
• Increased expression of TR positive targets in both hypothyroid and euthyroid conditions • Improved cholesterol tolerance due to diminished intestinal cholesterol absorption (as the result of changes in the composition and hydrophobicity of the bile salt pool) |
TR | (19–21) | |
| Global NCOR ΔRID knockin |
• Increased energy expenditure as a result of enhanced sensitivity to TH • Could rescue insulin-resistant phenotype of mutant TRβ |
TR | (22, 23) | |
| Global DADm knockin | • Leaner due to increased energy expenditure • Improved insulin-sensitivity • Abnormal circadian behavior due to aberrant regulation of clock genes • Altered oscillatory patterns of several metabolic genes • Derepressed TH-activated genes in euthyroid and hypothyroid mice liver |
TR LXR |
(24, 25) | |
| LKO (AAV8-TBG-Alb-Cre) |
• Developed hepatosteatosis due to increased lipogenesis | RevErb LXR |
(26) | |
| LKO (Alb-Cre) |
• Repressed lipid synthesis in the fasting state • Repressed fatty acid oxidation and ketogenesis in the feeding state • Improved liver regeneration after partial hepatectomy and blocked diethylnitrosamine (DEN)-induced hepatocarcinogenesis |
PPARα LXR ERRα |
(27, 28) | |
| LKO (Alb-Cre) |
• Developed hepatosteatosis due to increased lipogenesis | TR | (29) | |
| SMRT (Ncor2) |
Global KO | • Embryonic lethality before E16.5 due to lethal heart defect • Impaired neural development in forebrain • Fail to maintenance of the neural stem cell state |
RAR | (30) |
| Global SMRT mRID knockin | • Decreased energy expenditure • Developed global glucose tolerance and insulin sensitivity • Increased adiposity due to enhanced adipogenesis • Impaired type I pneumocytes differentiation and produced respiratoty distress syndrome at birth |
TR PPARγ |
(31) | |
| Global SMRTmRID1 knockin | • Accelerated aging (reduced mitochondrial function and increased susceptibility to oxidative stress) • Developed global glucose intolerance and insulin resistance • Upon HFD: • Obesity, insulin-insensitive, and refractory to the glucose lowering effects of TZD and AICAR, energy metabolism shifts from OxPhos to glycolysis • Mesenteric adipose tissue: adipocyte hypertrophy and increased inflammatory • Liver: hepatosteatosis • BAT: reduced thermogenic capacity and mitochondrial biogenesis |
RAR TR PPARα PPARγ |
(32, 33) | |
| LKO (AAV8-TBG-Alb-Cre) |
• No obvious metabolic phenotype | – | (26) | |
| LKO (Alb-Cre) |
• Little effect on most of TR targets in either euthyroid or hypothyroid animals • de-repressed RAR targets (Cyp26a1) |
RAR | (29) | |
| NCOR/SMRT (Ncor1/2) |
NCOR/SMRT LKO (Alb-Cre) | • Hepatosteatosis due to activated hepatic lipogenesis and lipid storage • Normal glucose sensitivity • Increased ChREBP isoforms expression |
TR RAR |
(29) |
| Global NS-DADm knockin | • Upregulated lipid-metabolic genes and mile hepatosteatosis • Undetectable HDAC3 enzyme activity, abrogated genome-wide HDAC3 recruitment, as well as increased local histone acetylation level |
Lipid-sensing NRs |
(34) | |
| HDAC3 (Hdac3) |
Global KO | • Embryonic lethality before E9.5 | (35) | |
| LKO (Mx1-Cre plus pIpC injection or Alb-Cre) |
• Hepatomegaly due to hepatocyte hypertrophy • Hepatosteatosis • Increased serum TG, total serum cholesterol, and LDL • Hypersensitive to insulin |
PPARγ2 | (36) | |
| LKO (AAV8-TBG-Alb-Cre) |
• Alteration in circadian genes • Hepatosteatosis due to increased lipogenesis and sequestration • Repressed gluconeogenesis • Improved insulin sensitivity |
RevErb HNF4α HNF6 |
(26, 34, 37–41) | |
| TBL1 (Tbl1x)TBLR1 (Tbl1xr1) |
Liver RNAi knockdown (adenovirus- delivered shRNA) | • Hepatosteatosis • Highly elevated VLDL TG • Inhibited of PPARα activity under both normal and HFD conditions |
PPARα | (42) |
| GPS2 (Gps2) |
Global KO | • Embryonic lethality around E10 | (43) | |
| LKO (Alb-Cre) |
• Dramatically reduced VLDL TG • Protected from HFD-induced hepatic steatosis and MCD-induced fibrosis • Enhanced PPARα-induced fatty acid oxidation |
PPARα | (44) | |
| PROX1 (Prox1) |
Liver RNAi knockdown (AAV8-TBG-shRNA) | • Significantly elevated hepatic TG | HNF4 | (41) |
| LKO (Alb-Cre) |
• Hepatic injury • Non-obese but insulin-resistant • Suppressed glycolysis • Upregulated both oxidative phosphorylation and autophagy |
Lipid-sensing NRs |
(45) | |
| RIP140 (Nrip1) |
Global KO | • Lean and resistance to HFD-induced obesity and hepatic steatosis • Increased oxygen consumption • Unaffected adipogenesis, increased certain lipogenic enzymes, and UCP1 in Adipose tissue • Inhibited lipogenesis and enhanced gluconeogenesis |
LXR | (46, 47) |
| Liver RNAi knockdown (adenovirus- delivered shRNA) |
• Alleviated hepatic steatosis in tumor-bearing, cachectic animals • Increased free fatty acid oxidation and ketogenesis • Enhanced VLDL secretion • Reduced peripheral lipoprotein lipase activity |
LXR PPARα |
(48) | |
| SHP (Nr0b2) |
Global KO | • Increased bile acids synthesis under chow diet • Dietary bile acids induce liver damage and restore feedback regulation • A synthetic FXR agonist is not hepatotoxic and has no regulatory effects • Cholestyramine enhanced the expression of CYP7A1 and CYP8B1 and reduced the bile acid pool |
LRH1 HNF4α LXR |
(49) |
| Global KO | • Increased bile acids synthesis under chow diet • No significant defects in cholesterol metabolism under chow diet • Bile acids still can suppress Cyp7a1 expression • Resistant to bile acid induced liver damage |
LRH1 HNF4α LXR |
(50, 51) | |
| Liver-specific overexpression | • Depleted of hepatic bile acid pool • Accumulated TG in liver |
FXR LRH1 HNF4α PPARγ SREBP1c |
(52) | |
| LKO (Alb-Cre) |
• De-repressed Cyp7a1 and Cyp8b1 under chow diet and cholesterol and cholic acid diet • Resistance to diet induced hypercholesterolemia |
Multiple NRs | (53) | |
| FXR SHP DLKO | • Cholestasis and liver injury as early as 3 weeks of age due to dysregulation of bile acid homeostatic genes • Activated C21 steroid biosynthesis pathway • Lower hepatic TG accumulation, improved glucose/insulin tolerance, and accelerated fatty acid use in aged mice |
Multiple NRs | (54, 55) |