Phenotypes Associated with This Genotype

Genotype
MGI:4829790

• Allelic Composition: Pten^tm1Hwu/Pten^tm1Hwu; Speer6-ps1^{Tg(Alb-cre)21Mgn}/Speer6-ps1⁺
• Genetic Background: involves: 129S4/SvJae * C57BL/6 * DBA

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

liver/biliary system

increased hepatocyte apoptosis ( J:218587 )

♂ • progressive hepatocyte cell death as mice progress from steatosis to premalignancy, with massive hepatocyte death by 9 months of age

increased hepatocyte proliferation ( J:218587 )

♂ • at 12 months of age, livers show increased cell proliferation

abnormal liver morphology ( J:218587 )

♂ • progressive and chronic liver injury that begins before proliferation of hepatic progenitors

♂ • accumulation of hepatic progenitor cells in the periductal region of livers from 9-12 months of age

♂ • liver shows multiple layers of progenitor cells surrounding a single layer of ductal cells which show high mitotic activity after 9 months of age

enlarged liver ( J:88441 , J:171445 )

• mutants exhibit enlarged, whitish livers containing large fat vacuoles by 12 weeks of age (J:171445)

• mutants treated with rapamycin show reduced hepatocyte cell size, thus reducing the liver:body weight ratio (J:171445)

increased liver weight ( J:88441 , J:160759 )

increased liver glycogen level ( J:88441 )

• increase in glycogen storage in the liver

increased liver triglyceride level ( J:88441 , J:160759 )

• 3-fold increase in triglyceride content in the liver (J:88441)

• however, normal levels of plasma triglycerides (J:88441)

• 2-4-fold increase of triglyceride content in the liver of 1 and 3 month old mutants, respectively (J:160759)

hepatic steatosis ( J:88441 , J:160759 , J:218587 )

• progressive development of fatty liver (J:88441)

♂ (J:218587)

macrovesicular hepatic steatosis ( J:171445 )

• mutants exhibit enlarged, whitish livers containing large fat vacuoles by 12 weeks of age

• mutants treated with rapamycin exhibit no differences in steatosis compared to vehicle-treated mutants

pale liver ( J:88441 )

increased cholangiocarcinoma incidence ( J:218587 )

♂ • tumors show compact trabecular growth patterns and pseudoglandular structures of hepatocellular carcinoma and tubular features of cholangiocyte carcinoma

increased liver tumor incidence ( J:218587 )

♂ • mice develop liver tumors starting at approximately 8-9 months of age

♂ • 50% of mice develop tumors between 9 and 12 months of age and 100% develop tumors by 12 months of age

♂ • tumors show mixed cell characteristics, with tumors composed of colangiocytes, hepatocytes, and bi-lineage cells

increased hepatocellular carcinoma incidence ( J:218587 )

♂ • tumors show compact trabecular growth patterns and pseudoglandular structures of hepatocellular carcinoma and tubular features of cholangiocyte carcinoma

adipose tissue

decreased total body fat amount ( J:88441 )

• 50% reduction in total body fat content

homeostasis/metabolism

decreased circulating glucose level ( J:88441 )

• decrease in fasting glucose levels at 1 and 3 months of age, however at 6 months of age, when severe steatosis is seen, the fasting glucose level is similar to wild-type

decreased circulating insulin level ( J:88441 )

• decrease in fasting plasma insulin levels at 3 and 6 months of age

decreased circulating leptin level ( J:88441 )

• decrease in serum leptin levels at one month of age

• however eating behavior is normal

increased circulating alanine transaminase level ( J:218587 )

♂ • serum alanine aminotransferase levels increase progressively, reaching 5-fold higher levels at 12 months of age

improved glucose tolerance ( J:88441 )

• increase in glucose clearance during an intraperitoneal glucose load

increased liver glycogen level ( J:88441 )

• increase in glycogen storage in the liver

increased insulin sensitivity ( J:88441 )

• increase in insulin sensitivity in the liver

abnormal fatty acids level ( J:88441 )

• hepatocyte fatty acid uptake by passive diffusion is increased by 20% compared to controls, however active transportation of fatty acid is not changed and thus total fatty acid uptake is not significantly altered

• rate of fatty acid synthesis is 2.5-fold higher in mutant livers than in controls

decreased circulating free fatty acids level ( J:88441 )

• 30% decrease in circulating free fatty acids

increased liver triglyceride level ( J:88441 , J:160759 )

• 3-fold increase in triglyceride content in the liver (J:88441)

• however, normal levels of plasma triglycerides (J:88441)

• 2-4-fold increase of triglyceride content in the liver of 1 and 3 month old mutants, respectively (J:160759)

impaired lipolysis ( J:88441 )

• decrease in lipolysis rate

growth/size/body

enlarged liver ( J:88441 , J:171445 )

• mutants exhibit enlarged, whitish livers containing large fat vacuoles by 12 weeks of age (J:171445)

• mutants treated with rapamycin show reduced hepatocyte cell size, thus reducing the liver:body weight ratio (J:171445)

increased liver weight ( J:88441 , J:160759 )

cellular

increased hepatocyte apoptosis ( J:218587 )

♂ • progressive hepatocyte cell death as mice progress from steatosis to premalignancy, with massive hepatocyte death by 9 months of age

increased hepatocyte proliferation ( J:218587 )

♂ • at 12 months of age, livers show increased cell proliferation

oxidative stress ( J:218587 )

♂ • marker analysis indicates oxidative stress in the liver

neoplasm

increased cholangiocarcinoma incidence ( J:218587 )

♂ • tumors show compact trabecular growth patterns and pseudoglandular structures of hepatocellular carcinoma and tubular features of cholangiocyte carcinoma

increased liver tumor incidence ( J:218587 )

♂ • mice develop liver tumors starting at approximately 8-9 months of age

♂ • 50% of mice develop tumors between 9 and 12 months of age and 100% develop tumors by 12 months of age

♂ • tumors show mixed cell characteristics, with tumors composed of colangiocytes, hepatocytes, and bi-lineage cells

increased hepatocellular carcinoma incidence ( J:218587 )

♂ • tumors show compact trabecular growth patterns and pseudoglandular structures of hepatocellular carcinoma and tubular features of cholangiocyte carcinoma

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
hepatocellular carcinoma		DOID:684	OMIM:114550	J:218587
steatotic liver disease		DOID:9452	OMIM:228100	J:216841