Phenotypes associated with this allele

• Allele Symbol: Abcb4^tm1Bor
• Allele Name: targeted mutation 1, Piet Borst
• Allele ID: MGI:1857236
• Summary: 9 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Abcb4^tm1Bor/Abcb4^tm1Bor	C.129P2-Abcb4^tm1Bor	MGI:5526018
hm2	Abcb4^tm1Bor/Abcb4^tm1Bor	CAnNCrl.12P2(FVB)-Abcb4^tm1Bor	MGI:5659501
hm3	Abcb4^tm1Bor/Abcb4^tm1Bor	either: (involves: 129P2/OlaHsd) or (involves: 129P2/OlaHsd * FVB/N)	MGI:2653844
hm4	Abcb4^tm1Bor/Abcb4^tm1Bor	FVB.129P2-Abcb4^tm1Bor/J	MGI:3840644
hm5	Abcb4^tm1Bor/Abcb4^tm1Bor	involves: 129P2/OlaHsd * BALB/c	MGI:5618431
hm6	Abcb4^tm1Bor/Abcb4^tm1Bor	involves: 129P2/OlaHsd * FVB/N	MGI:3694478
cn7	Abcb4^tm1Bor/Abcb4^tm1Bor Por^tm1Wolf/Por^tm1Wolf Speer6-ps1^Tg(Alb-cre)21Mgn/Speer6-ps1^+	involves: 129P2/OlaHsd * C57BL/6 * DBA * FVB/N	MGI:5618809
cx8	Abcb4^tm1Bor/Abcb4^tm1Bor Pemt^tm1J/Pemt^tm1J	involves: 129P2/OlaHsd * C57BL/6 * FVB/N	MGI:5618424
cx9	Abcb4^tm1Bor/Abcb4^tm1Bor Tg(ABCG5/ABCG8)14-2Hobb/0	involves: 129P2/OlaHsd * C57BL/6J * FVB/N * SJL	MGI:3840643

Genotype
MGI:5526018

hm1

• Allelic Composition: Abcb4^tm1Bor/Abcb4^tm1Bor
• Genetic Background: C.129P2-Abcb4^tm1Bor

• ♀: phenotype observed in females
• ♂: phenotype observed in males
• N: normal phenotype

homeostasis/metabolism

decreased circulating calcium level ( J:199949 )

increased circulating phosphate level ( J:199949 )

decreased vitamin D level ( J:199949 )

• 25(OH)-vitamin D serum concentrations are almost 50% lower than in wild-type mice

increased transforming growth factor beta level ( J:199949 )

• increase in serum levels of activated TGF-beta until the age of 30 weeks which subsequently declines to basal levels by 45 weeks of age compared to wild-type mice which show a continuous decrease throughout life

increased tumor necrosis factor (ligand) superfamily member 11 level ( J:199949 )

• increase in serum levels of the osteoclastogenesis inducing factor RANKL

abnormal enzyme/coenzyme activity ( J:199949 )

• elevation in serum activities of liver enzymes, including aminotransferase and alkaline phosphatase

increased alkaline phosphatase activity ( J:199949 )

liver/biliary system

liver fibrosis ( J:199949 )

• liver damage increases most rapidly in the first 15 weeks of life and then progresses slowly thereafter

skeleton

decreased bone mineral content ( J:199949 )

• reduction of whole body bone mineral content in males and of bone fractions of the total tissue weights in females at 15 weeks of age

• decrease in femoral mineral contents

decreased bone mineral density ( J:199949 )

♀ • females fed a vitamin D insufficient diet exhibit decreased cortical bone mineral density compared to wild-type mice on the same diet

♀ • vitamin D supplementation does not restore bone abnormalities

decreased bone mineral density of femur ( J:199949 )

♀ • females fed a vitamin D insufficient diet exhibit decreased femoral bone mineral density compared to wild-type mice on the same diet

♀ • vitamin D supplementation does not restore bone abnormalities

decreased bone volume ( J:199949 )

• decrease in femoral mineral contents and in total femoral volume at 15 weeks of age, thus total femoral volume bone mineral density is not affected

abnormal compact bone morphology ( J:199949 )

♀ • females exhibit a decrease in cortical bone density and a lower circumference of the bone at the exact mid-diaphysis (periosteal circumference), resulting in normal thickness of the cortical bone

abnormal trabecular bone morphology ( J:199949 )

• increase in trabecular separation at 20 weeks of age

• trabecular tissue mineral density is lower at 30 weeks of age

• with increasing age, changes in trabecular order and connectivity are seen with reduced mineralization of the trabecular bone meshwork

abnormal trabecular bone volume ( J:199949 )

• changes in trabecular bone volume fractions are seen at 5 weeks of age but not in older mice, however trabecular thickness does not differ from wild-type

decreased bone trabecula number ( J:199949 )

• decrease in trabecular numbers at 20 weeks of age

decreased trabecular bone connectivity density ( J:199949 )

• connective density is lower at 20 weeks of age

abnormal bone remodeling ( J:199949 )

• mutants exhibit altered gene expression of bone modeling markers and an increase in serum levels of the osteoclastogenesis inducing factor RANKL, indicating impaired bone remodeling

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
cholestasis		DOID:13580		J:199949

Genotype
MGI:5659501

hm2

• Allelic Composition: Abcb4^tm1Bor/Abcb4^tm1Bor
• Genetic Background: CAnNCrl.12P2(FVB)-Abcb4^tm1Bor

liver/biliary system

portal hypertension ( J:217802 )

• Background Sensitivity: mice on the BALB/cAnNCrl background show an earlier onset of severe portal hypertension than mice on the FVB/N background

• Background Sensitivity: portal pressure in mice on the BALB/cAnNCrl background increases at a higher pace compared to mice on the FVB/N background, peaking at 12 mmHg at 12 weeks compared to 8.2 mmHg in mice on the FVB/N background

increased hepatocellular carcinoma incidence ( J:217802 )

• Background Sensitivity: mice on the BALB/cAnNCrl background show accelerated development of primary liver cancer compared to mice on the FVB/N background, showing tumors starting at 7 months of age compared to 12 months of age on the FVB/N background

• Background Sensitivity: tumor burden in mice on the BALB/cAnNCrl background is higher than on the FVB/N background

• liver tumors are classified as hepatocellular carcinoma

liver cirrhosis ( J:217802 )

• Background Sensitivity: mice on the BALB/cAnNCrl background show accelerated development of cirrhosis compared to mice on the FVB/N background

liver fibrosis ( J:217802 )

• mice spontaneously develop periductal onion-skin type fibrotic lesions starting from 4 weeks of age

• Background Sensitivity: mice on the BALB/cAnNCrl background show accelerated liver fibrosis compared to mice on the FVB/N background, with signs of bridging fibrosis already at 8 weeks and thick septae formation by 12 weeks

• Background Sensitivity: collagen content in the liver of mice on the BALB/cAnNCrl background is higher at any time point studied compared to mice on the FVB/N background, with total hydroxyproline content about 3-fold higher in the liver than in mice on the FVB/N background

• Background Sensitivity: fibrotic matrix in mice on the BALB/cAnNCrl background is cross-linked to a greater degree than in mice on the FVB/N background

• Background Sensitivity: males exhibit more severe fibrosis than females

• Background Sensitivity: marker analysis indicates that fibrogenic cell activation is amplified in mice on the BALB/cAnNCrl background compared to the FVB/N background

• prominent sinusoidal fibrosis starting at 8 weeks of age

neoplasm

increased hepatocellular carcinoma incidence ( J:217802 )

• Background Sensitivity: mice on the BALB/cAnNCrl background show accelerated development of primary liver cancer compared to mice on the FVB/N background, showing tumors starting at 7 months of age compared to 12 months of age on the FVB/N background

• Background Sensitivity: tumor burden in mice on the BALB/cAnNCrl background is higher than on the FVB/N background

• liver tumors are classified as hepatocellular carcinoma

cardiovascular system

portal hypertension ( J:217802 )

• Background Sensitivity: mice on the BALB/cAnNCrl background show an earlier onset of severe portal hypertension than mice on the FVB/N background

• Background Sensitivity: portal pressure in mice on the BALB/cAnNCrl background increases at a higher pace compared to mice on the FVB/N background, peaking at 12 mmHg at 12 weeks compared to 8.2 mmHg in mice on the FVB/N background

growth/size/body

weight loss ( J:217802 )

• mice lose weight at 12 months of age with a 21.5% reduction in weight compared to 2.9% in wild-type mice

enlarged spleen ( J:217802 )

hematopoietic system

enlarged spleen ( J:217802 )

homeostasis/metabolism

increased circulating bilirubin level ( J:217802 )

• Background Sensitivity: total bilirubin in serum of aged mice on the BALB/cAnNCrl background is higher at 7 months of age compared to mice on the FVB/N background, and continues to increase through 12 months of age

increased circulating alanine transaminase level ( J:217802 )

• increase in serum alanine aminotransferase is similar on both the BALB/cAnNCrl and FVB/N backgrounds

increased circulating alkaline phosphatase level ( J:217802 )

• Background Sensitivity: serum levels of alkaline phosphatase are higher on the BALB/cAnNCrl background and increase with age compared to mice on the FVB/N background which show a decrease in levels by 12 weeks

increased circulating aspartate transaminase level ( J:217802 )

• increase in serum aspartate aminotransferase is similar on both the BALB/cAnNCrl and FVB/N backgrounds

immune system

enlarged spleen ( J:217802 )

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
primary sclerosing cholangitis		DOID:0060643	OMIM:613806	J:217802

Genotype
MGI:2653844

hm3

• Allelic Composition: Abcb4^tm1Bor/Abcb4^tm1Bor
• Genetic Background: either: (involves: 129P2/OlaHsd) or (involves: 129P2/OlaHsd * FVB/N)

reproductive system

reduced female fertility ( J:21232 )

♀ • at 4 months

liver/biliary system

abnormal hepatobiliary system morphology ( J:21232 )

abnormal bile duct morphology ( J:15531 )

• portal expansion due to ductular proliferation is seen

bile duct proliferation ( J:21232 )

• mice exhibit ductular proliferation and portal inflammation with mixed inflammatory infiltrate unlike in wild-type mice

dilated bile duct ( J:15531 )

• larger bile ducts are dilated

enlarged liver ( J:21232 )

• beginning at 4 to 6 months

abnormal bile canaliculus morphology ( J:15531 , J:21232 )

• prominent widening and increased tortuosity of bile canaliculi with loss of microvilli is present (J:15531)

• bile canaliculi fail to mature remaining wide and smooth unlike in wild-type mice (J:21232)

abnormal hepatocyte morphology ( J:15531 )

• hepatocyte degeneration, irregular size with nuclear polymorphism and focal necrosis are observed, along with increased proliferation

abnormal portal triad morphology ( J:21232 )

• at 3 months, mice exhibit expansion of the portal triad unlike in wild-type mice

hepatic necrosis ( J:21232 )

• beginning at 4 to 6 months

increased hepatocellular carcinoma incidence ( J:21232 )

• beginning at 4 to 6 months, mice develop hepatocellular carcinoma with necrosis, hemorrhage, and strong cytonuclear polymorphism unlike in wild-type mice

• mice exhibit lung metastasis

abnormal hepatobiliary system physiology ( J:21232 )

liver hemorrhage ( J:21232 )

• beginning at 4 to 6 months

bile duct inflammation ( J:15531 , J:21232 )

• inflammation of bile ducts (J:15531)

liver inflammation ( J:15531 )

• portal inflammation with mixed inflammatory infiltrate and slight fibrosis

abnormal bile secretion ( J:15531 )

biliary cirrhosis ( J:21232 )

• at 3 months, mice exhibit biliary cirrhosis with porto-portal fibrous septa unlike in wild-type mice

cholestasis ( J:21232 )

intrahepatic cholestasis ( J:15531 )

• moderate liver damage with cholestatic properties (raised serum-conjugated bilirubin) is observed

abnormal bile composition ( J:15531 )

• absence of phospholipid secretion in bile, lipid secretion is decreased and there is a 15-reduction in cholesterol secretion in bile

• glutathione secretion in bile is ~14% of wild-type

• chloride secretion is slightly, but significantly, elevated

• phospolipid to bile salt ratio is only ~41% of wild-type

homeostasis/metabolism

abnormal blood homeostasis ( J:15531 )

• serum is yellowish, suggesting liver damage

abnormal circulating bilirubin level ( J:15531 )

• 12-fold elevated bilirubin level; ~50% of this is conjugated

abnormal circulating alanine transaminase level ( J:15531 )

• 5.8-fold increase in alanine transaminase level

abnormal circulating alkaline phosphatase level ( J:15531 )

• 3-fold increase in serum alkaline phosphatase level

abnormal circulating aspartate transaminase level ( J:15531 )

• 4-fold increase in aspartate transaminase level

neoplasm

increased hepatocellular carcinoma incidence ( J:21232 )

• beginning at 4 to 6 months, mice develop hepatocellular carcinoma with necrosis, hemorrhage, and strong cytonuclear polymorphism unlike in wild-type mice

• mice exhibit lung metastasis

immune system

bile duct inflammation ( J:15531 , J:21232 )

• inflammation of bile ducts (J:15531)

liver inflammation ( J:15531 )

• portal inflammation with mixed inflammatory infiltrate and slight fibrosis

endocrine/exocrine glands

abnormal bile duct morphology ( J:15531 )

• portal expansion due to ductular proliferation is seen

bile duct proliferation ( J:21232 )

• mice exhibit ductular proliferation and portal inflammation with mixed inflammatory infiltrate unlike in wild-type mice

dilated bile duct ( J:15531 )

• larger bile ducts are dilated

cardiovascular system

liver hemorrhage ( J:21232 )

• beginning at 4 to 6 months

growth/size/body

enlarged liver ( J:21232 )

• beginning at 4 to 6 months

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
hepatocellular carcinoma		DOID:684	OMIM:114550	J:21232

Genotype
MGI:3840644

hm4

• Allelic Composition: Abcb4^tm1Bor/Abcb4^tm1Bor
• Genetic Background: FVB.129P2-Abcb4^tm1Bor/J

homeostasis/metabolism

homeostasis/metabolism phenotype ( J:100491 )

N • mice exhibit normal plasma levels of sitosterol and campesterol

abnormal feces lipid level ( J:100491 )

• fecal acidic sterol levels are decreased 30% compared to in wild-type mice

• however, fecal neutral sterol levels are normal

increased circulating bilirubin level ( J:105357 , J:217802 )

• slight increase (J:105357)

• Background Sensitivity: total bilirubin in serum of aged mice on the FVB/N background is lower at 7 months of age compared to mice on the BALB/cAnNCrl background (J:217802)

abnormal circulating enzyme level ( J:105357 )

• elevated serum transaminase levels

increased circulating alanine transaminase level ( J:100491 , J:217802 )

• increase in serum alanine aminotransferase is similar on both the BALB/cAnNCrl and FVB/N backgrounds (J:217802)

increased circulating alkaline phosphatase level ( J:105357 , J:217802 )

• Background Sensitivity: serum levels of alkaline phosphatase are lower on the FVB/N background and show a decrease in levels by 12 weeks compared to mice on the BALB/cAnNCrl background in which levels increase with age (J:217802)

increased circulating aspartate transaminase level ( J:100491 , J:217802 )

• increase in serum aspartate aminotransferase is similar on both the BALB/cAnNCrl and FVB/N backgrounds (J:217802)

cardiovascular system

portal hypertension ( J:217802 )

• Background Sensitivity: mice on the FVB/N background show a later onset of severe portal hypertension than mice on the BALB/cAnNCrl background

• Background Sensitivity: portal pressure in mice on the FVB/N background increases at a slower pace compared to mice on the BALB/cAnNCrl background

liver/biliary system

portal hypertension ( J:217802 )

• Background Sensitivity: mice on the FVB/N background show a later onset of severe portal hypertension than mice on the BALB/cAnNCrl background

• Background Sensitivity: portal pressure in mice on the FVB/N background increases at a slower pace compared to mice on the BALB/cAnNCrl background

abnormal bile duct morphology ( J:105357 )

• mice exhibit proliferation of bile ducts, accompanied by periportal and periductal fibrosis, resulting in fibro-obliteration and segmental strictures of bile duct

• 42% of 7-10 month old females, but not males, develop choledocholithiasis (bile duct stones)

dilated bile duct ( J:105357 )

♀ • dilated extrahepatic duct in 7 month old females

abnormal gallbladder size ( J:105357 )

• gallbladders are 3 times larger than in wild-type mice at 9 weeks of age

• over time, gallbladder size decreases in males, but not females, such that at 18 weeks of age, some males at 18 weeks of age have very small gallbladders filled with sticky mucin gel and needle-like crystals

bile duct inflammation ( J:105357 )

• progressive sclerosing cholangitis

gallstones ( J:105357 )

• 50% and 80% of females at 12 and 15 weeks of age, respectively, exhibit gallstones in the gallbladder biles and by 18 weeks, all females have gallstones

• males form gallstones later, after 15 weeks of age, and with lower prevalence rates than in females

• core of stones are composed of needle-like crystals and gelled mucin

• number of gallstones per mouse ranges from 1-8 with an average of 1.3 +/- 0.3 stones per mouse and most gallstones are smaller than 0.1 mm

• stone number and size are higher in females than males

• 42% of 7-10 month old females, but not males, develop choledocholithiasis

abnormal liver morphology ( J:105357 )

• cholestatic liver damage

• mature mice develop intrahepatic stones, which are composed of needle-like crystals like the gallbladder stones

enlarged liver ( J:105357 )

increased hepatocellular carcinoma incidence ( J:217802 )

• Background Sensitivity: mice on the FVB/N background show slower development of primary liver cancer compared to mice on the BALB/cAnNCrl background, showing tumors starting at 12 months of age compared to 7 months of age on the BALB/cAnNCrl background

• Background Sensitivity: tumor burden in mice on the FVB/N background is lower than on the BALB/cAnNCrl background

• liver tumors are classified as hepatocellular carcinoma

liver cirrhosis ( J:217802 )

• Background Sensitivity: mice on the FVB/N background show slower development of cirrhosis compared to mice on the BALB/cAnNCrl background

liver fibrosis ( J:217802 )

• mice spontaneously develop periductal onion-skin type fibrotic lesions starting from 4 weeks of age

• Background Sensitivity: mice on the FVB/N background show slower progression of liver fibrosis compared to mice on the BALB/cAnNCrl background

• Background Sensitivity: collagen content in the liver of mice on the FVB/N background is lower at any time point studied compared to mice on the BALB/cAnNCrl background

• Background Sensitivity: fibrotic matrix in mice on the FVB/N background is cross-linked to a lesser degree than in mice on the BALB/cAnNCrl background

• Background Sensitivity: females exhibit more severe fibrosis than males

• Background Sensitivity: marker analysis indicates that fibrogenic cell activation is lower in mice on the FVB/N BALB/cAnNCrl background compared to the BALB/cAnNCrl background

• prominent sinusoidal fibrosis starting at 8 weeks of age

intrahepatic cholestasis ( J:105357 )

• occluded intrahepatic bile ducts filled with crystalline occlusions composed of needle-like crystals and mucin gel

abnormal bile composition ( J:100491 , J:105357 )

• bile cholesterol levels are decreased compared to in wild-type mice (J:100491)

• gallbladder bile precipitates solid crystals, with males forming these needle-like crystals later (after 15 weeks) than females (after 12 weeks of age) and with a lower prevalence than in females (J:105357)

• 33% and 60% of females at 12 and 15 weeks of age, respectively, exhibit needle-like crystals in the gallbladder biles (J:105357)

• phosphatidylcholine (PC) concentrations in the gallbladder biles are decreased, and the relative compositions shift to greater proportions of the more hydrophobic PC-(18:0-18:2) and PC-(18:0-20:4) (J:105357)

• females exhibit a more hydrophobic bile salt pool due to lower tauro-beta-muricholate levels in bile (J:105357)

hematopoietic system

enlarged spleen ( J:217802 )

neoplasm

increased hepatocellular carcinoma incidence ( J:217802 )

• Background Sensitivity: mice on the FVB/N background show slower development of primary liver cancer compared to mice on the BALB/cAnNCrl background, showing tumors starting at 12 months of age compared to 7 months of age on the BALB/cAnNCrl background

• Background Sensitivity: tumor burden in mice on the FVB/N background is lower than on the BALB/cAnNCrl background

• liver tumors are classified as hepatocellular carcinoma

digestive/alimentary system

abnormal feces lipid level ( J:100491 )

• fecal acidic sterol levels are decreased 30% compared to in wild-type mice

• however, fecal neutral sterol levels are normal

endocrine/exocrine glands

abnormal bile duct morphology ( J:105357 )

• mice exhibit proliferation of bile ducts, accompanied by periportal and periductal fibrosis, resulting in fibro-obliteration and segmental strictures of bile duct

• 42% of 7-10 month old females, but not males, develop choledocholithiasis (bile duct stones)

dilated bile duct ( J:105357 )

♀ • dilated extrahepatic duct in 7 month old females

abnormal gallbladder size ( J:105357 )

• gallbladders are 3 times larger than in wild-type mice at 9 weeks of age

• over time, gallbladder size decreases in males, but not females, such that at 18 weeks of age, some males at 18 weeks of age have very small gallbladders filled with sticky mucin gel and needle-like crystals

immune system

enlarged spleen ( J:217802 )

bile duct inflammation ( J:105357 )

• progressive sclerosing cholangitis

growth/size/body

enlarged liver ( J:105357 )

enlarged spleen ( J:217802 )

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
cholecystitis		DOID:1949	OMIM:600803	J:105357

Genotype
MGI:5618431

hm5

• Allelic Composition: Abcb4^tm1Bor/Abcb4^tm1Bor
• Genetic Background: involves: 129P2/OlaHsd * BALB/c

immune system

bile duct inflammation ( J:168123 )

• mice develop sclerosing cholangitis

• propranolol treatment reduces inflammation

liver/biliary system

bile duct inflammation ( J:168123 )

• mice develop sclerosing cholangitis

• propranolol treatment reduces inflammation

liver fibrosis ( J:168123 )

• mice develop periportal fibrosis after 3 months of age, characterized by onion skin-like matrix formation around the bile ducts

• after 5 months, septal formation and massive matrix deposition is seen around ducts in the liver and at 8 months, periportal fibrosis is frequently accompanied by septae formation and prominent proliferation of the bile ducts

• propranolol treatment improves liver architecture and reduces inflammation and fibrosis progression

cardiovascular system

decreased systemic arterial systolic blood pressure ( J:168123 )

• mice treated with propranolol long-term show a minor reduction in the average systolic blood pressure without impact on viability

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
primary sclerosing cholangitis		DOID:0060643	OMIM:613806	J:168123

Genotype
MGI:3694478

hm6

• Allelic Composition: Abcb4^tm1Bor/Abcb4^tm1Bor
• Genetic Background: involves: 129P2/OlaHsd * FVB/N

homeostasis/metabolism

increased circulating bilirubin level ( J:114411 )

abnormal circulating enzyme level ( J:114411 )

increased circulating alanine transaminase level ( J:114411 , J:175015 )

increased circulating aspartate transaminase level ( J:114411 )

abnormal sodium ion homeostasis ( J:175015 )

• sodium concentrations in the ileal lumen are increased

abnormal lipid homeostasis ( J:114411 )

decreased feces bile salt level ( J:175015 )

• daily bile acid disposal in feces is decreased

decreased intestinal cholesterol absorption ( J:114411 )

• 40% reduction in absorption efficiency

decreased circulating cholesterol level ( J:114411 )

• plasma levels reduced

increased bile salt level ( J:175015 )

• increase in concentration of bile acids in the plasma and the liver

• pool size of bile acids is increased

digestive/alimentary system

decreased feces bile salt level ( J:175015 )

• daily bile acid disposal in feces is decreased

decreased intestinal cholesterol absorption ( J:114411 )

• 40% reduction in absorption efficiency

abnormal intestine physiology ( J:175015 )

• mice exhibit an increase in taurocholic acid uptake in the ileum, indicating an increase in bile acid uptake

• sodium concentrations in the ileal lumen are increased

immune system

bile duct inflammation ( J:175015 )

• cholangitis

liver inflammation ( J:175015 )

• portal inflammation

liver/biliary system

bile duct inflammation ( J:175015 )

• cholangitis

liver inflammation ( J:175015 )

• portal inflammation

abnormal hepatocyte morphology ( J:175015 )

• hepatocytes show irregular nuclear polymorphism

focal hepatic necrosis ( J:175015 )

• focal necrosis with formation of eosinophilic bodies

intrahepatic cholestasis ( J:175015 )

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
intrahepatic cholestasis		DOID:1852		J:175015

Genotype
MGI:5618809

cn7

• Allelic Composition: Abcb4^tm1Bor/Abcb4^tm1Bor; Por^tm1Wolf/Por^tm1Wolf; Speer6-ps1^{Tg(Alb-cre)21Mgn}/Speer6-ps1⁺
• Genetic Background: involves: 129P2/OlaHsd * C57BL/6 * DBA * FVB/N

endocrine/exocrine glands

bile duct proliferation ( J:215915 )

• mice fed a cholic acid-supplemented diet for 8 weeks exhibit bile duct proliferation

growth/size/body

growth/size/body region phenotype ( J:215915 )

N • mice fed a 0.03% cholic acid-supplemented diet directly from weaning exhibit normal growth

increased liver weight ( J:215915 )

• mice fed a cholic acid-supplemented diet for 8 weeks exhibit an increased liver to body weight ratio

cellular

increased hepatocyte proliferation ( J:215915 )

• mice fed a cholic acid-supplemented diet for 8 weeks exhibit increased hepatocyte proliferation

homeostasis/metabolism

increased circulating bilirubin level ( J:215915 )

• plasma bilirubin levels are mildly increased at weaning and are further increased after 8 weeks of 0.03% cholic acid-supplemented diet

increased circulating alanine transaminase level ( J:215915 )

• plasma alanine transaminase levels are strongly elevated after 8 weeks of cholic acid-supplemented diet

increased circulating alkaline phosphatase level ( J:215915 )

• plasma alkaline phosphatase levels are strongly elevated after 8 weeks of cholic acid-supplemented diet

abnormal bile salt homeostasis ( J:215915 )

• on a cholic acid-supplemented diet, plasma bile salts predominantly consist of about 90% taurocholate (TC) and about 7% tauro-beta-muricholate (TbetaMC) compared to about 60% TC and 23% TbetaMC in single Abcb4 homozygotes

• on a cholic acid-supplemented diet, biliary bile salts predominantly consist of about 90% TC and about 2.5% of the secondary bile salt taurochenodeoxycholate (TDC) compared to 75% TC and 20% TbetaMC in single Abcb4 homozygotes

• on a cholic acid-supplemented diet, the biliary hydrophobicity index, but not the plasma hydrophobicity index, is elevated, indicating a more hydrophobic biliary bile salt pool

• however, mice fed a cholic acid-supplemented diet for 8 weeks exhibit normal bile flow and biliary bile salt output

increased bile salt level ( J:215915 )

• plasma bile salt levels are strongly elevated after 8 weeks of cholic acid-supplemented diet

liver/biliary system

increased hepatocyte proliferation ( J:215915 )

• mice fed a cholic acid-supplemented diet for 8 weeks exhibit increased hepatocyte proliferation

bile duct proliferation ( J:215915 )

• mice fed a cholic acid-supplemented diet for 8 weeks exhibit bile duct proliferation

increased liver weight ( J:215915 )

• mice fed a cholic acid-supplemented diet for 8 weeks exhibit an increased liver to body weight ratio

liver fibrosis ( J:215915 )

• mice fed a regular diet exhibit portal fibrosis

• mice fed a cholic acid-supplemented diet for 8 weeks exhibit portal fibrosis that is more severe than in single Abcb4 homozygotes

cholestasis ( J:215915 )

• mice fed a cholic acid-supplemented diet for 8 weeks develop a severe cholestatic phenotype with severe liver damage

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
intrahepatic cholestasis		DOID:1852		J:215915

Genotype
MGI:5618424

cx8

• Allelic Composition: Abcb4^tm1Bor/Abcb4^tm1Bor; Pemt^tm1J/Pemt^tm1J
• Genetic Background: involves: 129P2/OlaHsd * C57BL/6 * FVB/N

liver/biliary system

liver/biliary system phenotype ( J:175015 )

N • the liver damage that is seen in single Abcb4 homozygotes is attenuated with livers showing fewer hepatocytes with irregular nuclear polymorphism, less focal necrosis with formation of eosinophilic bodies, less portal inflammation, and less cholangitis

digestive/alimentary system

increased feces bile salt level ( J:175015 )

• bile acid disposal on feces is increased compared to single Abcb4 homozygotes

abnormal intestine physiology ( J:175015 )

• bile acid uptake in the ileum is decreased compared to single Abcb4 homozygotes and this impaired re-absorption of bile acids is due to lower concentration of sodium in the ileal segment of the small intestine

homeostasis/metabolism

increased feces bile salt level ( J:175015 )

• bile acid disposal on feces is increased compared to single Abcb4 homozygotes

decreased circulating alanine transaminase level ( J:175015 )

• plasma alanine transaminase activity is about 70% lower than in single Abcb4 homozygotes

decreased bile salt level ( J:175015 )

• concentration of bile acids in the plasma is about 50% lower than in single Abcb4 homozygotes

• bile acid content in livers is lower than in single Abcb4 homozygotes

• pool size of bile acids is reduced compared to single Abcb4 homozygotes

Genotype
MGI:3840643

cx9

• Allelic Composition: Abcb4^tm1Bor/Abcb4^tm1Bor; Tg(ABCG5/ABCG8)14-2Hobb/0
• Genetic Background: involves: 129P2/OlaHsd * C57BL/6J * FVB/N * SJL

homeostasis/metabolism

homeostasis/metabolism phenotype ( J:100491 )

N • plasma sitosterol and campesterol levels are normal

decreased intestinal cholesterol absorption ( J:100491 )

increased circulating alanine transaminase level ( J:100491 )

increased circulating aspartate transaminase level ( J:100491 )

liver/biliary system

abnormal bile composition ( J:100491 )

• bile cholesterol levels are decreased compared to in wild-type mice

digestive/alimentary system

abnormal feces composition ( J:100491 )

• fecal acidic sterol levels are decreased 30% compared to in wild-type mice

decreased intestinal cholesterol absorption ( J:100491 )