Phenotypes Associated with This Genotype

Genotype
MGI:5702658

• Allelic Composition: Pten^tm2Mak/Pten^tm2Mak; Speer6-ps1^{Tg(Alb-cre)21Mgn}/Speer6-ps1⁺
• Genetic Background: involves: 129P2/OlaHsd * C57BL/6 * C57BL/6J * DBA

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

growth/size/body

enlarged liver ( J:90905 )

• liver is larger in 10 week old mice and further enlarged at 40 weeks

increased liver weight ( J:90905 )

• liver weight per body weight ratio is increased 2-fold at 10 weeks and 3-fold at 40 weeks

liver/biliary system

abnormal liver sinusoid morphology ( J:90905 )

• mild sinusoidal fibrogenic changes and accumulations of lobular inflammatory cells are seen by 40 weeks of age

increased hepatocyte proliferation ( J:90905 )

• increase in hepatocyte proliferation at 10 weeks of age

• however, no differences in hepatocyte apoptosis are seen at 10 or 40 weeks of age

enlarged liver ( J:90905 )

• liver is larger in 10 week old mice and further enlarged at 40 weeks

increased liver weight ( J:90905 )

• liver weight per body weight ratio is increased 2-fold at 10 weeks and 3-fold at 40 weeks

increased liver triglyceride level ( J:90905 )

• triglyceride levels are increased in the liver at 10 weeks of age and are highly elevated at 40 weeks of age

• however, no differences in liver levels of free fatty acids, free cholesterol, or phospholipids are seen

abnormal hepatocyte morphology ( J:90905 )

• hepatocytes acquire expression of an adipocyte-specific marker

Mallory bodies ( J:90905 )

• Mallory bodies are frequently seen in hepatocytes by 40 weeks of age

increased hepatocyte number ( J:90905 )

• absolute numbers of total liver cells are almost normal at 10 weeks of age but increased by 1.5-fold at 40 weeks

microvesicular hepatic steatosis ( J:90905 )

• cytoplasm of liver cells is weakly eosinophilic and contains numerous microvesicular vacuoles containing lipids at 10 weeks of age; vacuolar changes are seen mainly around the central vein

• steatotic changes are more prominent in male than female mice

• by 40 weeks of age, livers show fatty changes of increased severity throughout the hepatic lobule such that aged liver resembles adipocytes in fat tissues

• however, no fibrotic changes are seen in the liver

pale liver ( J:90905 )

• livers are light-colored at 10 weeks of age and homogenously white in color at 40 weeks

increased hepatocellular carcinoma incidence ( J:90905 )

• hepatocellular carcinomas are seen in 5 of 6 males and 3 of 6 females; the hepatocellular carcinomas develop within liver adenomas and contain many fewer cytoplasmic lipid droplets than the adenomas

increased liver adenoma incidence ( J:90905 )

• macroscopic hepatic tumors are present in 66% of male and 30% of female mice at 40-44 weeks of age; nodular lesions resemble liver adenomas and cells with large droplets in the cytoplasm are prominent in most adenomas

homeostasis/metabolism

abnormal cellular cholesterol metabolism ( J:90905 )

• cholesterol ester levels are increased in the liver at 10 weeks of age and are highly elevated at 40 weeks of age

decreased fasting circulating glucose level ( J:90905 )

• glucose levels are lower in fasted mutants both before and after oral glucose administration

decreased circulating insulin level ( J:90905 )

• serum insulin levels are reduced at 12 weeks of age

increased circulating alanine transaminase level ( J:90905 )

• serum levels are elevated at 40 weeks of age but not at 10 weeks of age

increased circulating alkaline phosphatase level ( J:90905 )

• serum levels are elevated at 40 weeks of age but not at 10 weeks of age

increased circulating aspartate transaminase level ( J:90905 )

• serum levels are elevated at 40 weeks of age but not at 10 weeks of age

increased insulin sensitivity ( J:90905 )

• intraperitoneal insulin injection reduces glucose levels by a greater amount than in wild-type mice indicating insulin hypersensitivity

increased saturated fatty acids level ( J:90905 )

• 16-carbon monosaturated fatty acids (C16:1) and C18:1 fatty acids are increased in livers of 10 week old mice and C16:0, C16:1, C18:0, C18:1, and C18:2 fatty acids are increased in livers of 40 week old mice

increased liver triglyceride level ( J:90905 )

• triglyceride levels are increased in the liver at 10 weeks of age and are highly elevated at 40 weeks of age

• however, no differences in liver levels of free fatty acids, free cholesterol, or phospholipids are seen

neoplasm

increased hepatocellular carcinoma incidence ( J:90905 )

• hepatocellular carcinomas are seen in 5 of 6 males and 3 of 6 females; the hepatocellular carcinomas develop within liver adenomas and contain many fewer cytoplasmic lipid droplets than the adenomas

increased liver adenoma incidence ( J:90905 )

• macroscopic hepatic tumors are present in 66% of male and 30% of female mice at 40-44 weeks of age; nodular lesions resemble liver adenomas and cells with large droplets in the cytoplasm are prominent in most adenomas

increased metastatic potential ( J:90905 )

• 2 mutants with hepatocellular carcinoma show lung metastasis

cardiovascular system

abnormal liver sinusoid morphology ( J:90905 )

• mild sinusoidal fibrogenic changes and accumulations of lobular inflammatory cells are seen by 40 weeks of age

cellular

increased hepatocyte proliferation ( J:90905 )

• increase in hepatocyte proliferation at 10 weeks of age

• however, no differences in hepatocyte apoptosis are seen at 10 or 40 weeks of age

abnormal cellular cholesterol metabolism ( J:90905 )

• cholesterol ester levels are increased in the liver at 10 weeks of age and are highly elevated at 40 weeks of age

oxidative stress ( J:90905 )

• hepatic hydrogen peroxide levels in the liver are increased 7-fold, indicating increased production of reactive oxygen species

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
hepatocellular carcinoma		DOID:684	OMIM:114550	J:90905
steatotic liver disease		DOID:9452	OMIM:228100	J:90905