All Phenotypes Hmgcr<tm2Ishi> MGI Mouse

premature death ( J:201488 )

• ~30% of females survive until 12 months of age

• the survival rate of females is significantly higher than that of males

postnatal lethality, incomplete penetrance ( J:201488 )

• although born at a normal Mendelian frequency, 96% of males die with a median survival time of 35 days, whereas 71% of females die with a median survival time of 36 days

• no death occurs until 40 days of age in mice supplemented with mevalonate

• glucose supplementation dramatically improves the mortality of both sexes (96% versus 13% in males, and 71% versus 15% in females), indicating that hypoglycemia is the direct cause of lethality

weight loss ( J:201488 )

• although body weight is normal at 3 weeks of age, it decreases by 10% at 4 weeks and by 38% at 5 weeks of age

enlarged liver ( J:201488 )

• at 5 weeks of age, livers are enlarged

increased liver weight ( J:201488 )

• although liver weight is normal, the ratio of liver weight to body weight is increased by 39% and 74% at 4 and 5 weeks of age, respectively

enlarged liver ( J:201488 )

• at 5 weeks of age, livers are enlarged

increased liver weight ( J:201488 )

• although liver weight is normal, the ratio of liver weight to body weight is increased by 39% and 74% at 4 and 5 weeks of age, respectively

decreased liver cholesterol level ( J:201488 )

• at 4 weeks of age, hepatic total cholesterol content is decreased by only 22%

• in culture, cholesterol synthesis in liver slices is reduced by 45%

increased liver triglyceride level ( J:201488 )

• at 4 weeks of age, hepatic triglyceride contents are increased 2-fold, indicating that neutral lipids stained with oil-red O in the liver are predominantly triglycerides

abnormal liver parenchyma morphology ( J:201488 )

• at 5 weeks of age, H&E staining showed moderate to severe ballooning and unicellular necrosis of liver parenchymal cells

• Oil-red O staining showed moderate to severe microvesicular steatosis of the parenchymal cells

• liver pathology is milder at 4 weeks than that at 5 weeks of age

• mice that survive the lethal period still exhibit hepatocyte ballooning

• liver pathology is almost completely reversed by supplementation with mevalonate

hepatic necrosis ( J:201488 )

• unicellular necrosis of parenchymal cells at 5 weeks of age

microvesicular hepatic steatosis ( J:201488 )

• moderate to severe microvesicular steatosis of liver parenchymal cells at 5 weeks of age

• hepatic steatosis is completely reversed by providing mice with mevalonate

pale liver ( J:201488 )

• at 5 weeks of age, livers appear paler and whiter than control livers

abnormal liver physiology ( J:201488 )

• at 5 weeks of age, TUNEL-positive and Ki-67-positive liver parenchymal cells are significantly increased 11- and 2.8-fold, respectively, relative to control mice

• caspase 3 activity in the liver is increased 1.8-fold at 5 weeks of age

• however, caspase 8 activity and hydrogen peroxide (H2O2) levels are not significantly altered

jaundice ( J:201488 )

• at 5 weeks of age

liver failure ( J:201488 )

• at 5 weeks of age

increased circulating bilirubin level ( J:201488 )

• at 5 weeks of age, plasma levels of bilirubin are significantly increased

• the hyperbilirubinemia phenotype is normalized by supplementation with mevalonate

hypoglycemia ( J:201488 )

• moderately hypoglycemic at 5 weeks of age

decreased circulating cholesterol level ( J:201488 )

• at 3 weeks of age, total cholesterol levels in the plasma are decreased by 26%

increased circulating cholesterol level ( J:201488 )

• at 5 weeks of age, the plasma levels of total cholesterol and free cholesterol are increased 4.3-, 7.9-fold, respectively; in contrast, plasma cholesterol ester levels are decreased by 38%

• at 5 weeks of age, ratios of free cholesterol to cholesterol ester are increased 13-fold

• the hypercholesterolemia phenotype is almost normalized in mice supplemented with mevalonate

increased circulating phospholipid level ( J:201488 )

• at 5 weeks of age, the plasma levels of phospholipids are increased 4.0-fold

decreased circulating triglyceride level ( J:201488 )

• plasma triglyceride levels are decreased by 69% and 70% at 4 and 5 weeks of age, respectively

abnormal circulating lipoprotein level ( J:201488 )

• at 5 weeks of age, agar gel electrophoresis of plasma revealed that both lipoprotein X and apoB-48-containing lipoproteins are increased

decreased circulating LDL cholesterol level ( J:201488 )

• at 3 weeks of age, plasma concentrations of LDL cholesterol are decreased

increased circulating LDL cholesterol level ( J:201488 )

• at 5 weeks of age, most of the increased cholesterol is distributed in the size of very low-density lipoprotein through LDL

abnormal circulating apolipoprotein level ( J:201488 )

• at 3 weeks of age, plasma concentrations of apolipoprotein (apo) B-100 protein are decreased

• at 5 weeks of age, apoB-100 levels remain decreased, whereas plasma apoB-48 levels are substantially increased

increased circulating alanine transaminase level ( J:201488 )

• at 5 weeks of age, plasma levels of alanine transaminase are significantly increased

• ALT levels are almost normalized by supplementation with mevalonate

increased circulating aspartate transaminase level ( J:201488 )

• at 5 weeks of age, plasma levels of aspartate aminotransferase are significantly increased

decreased liver cholesterol level ( J:201488 )

• at 4 weeks of age, hepatic total cholesterol content is decreased by only 22%

• in culture, cholesterol synthesis in liver slices is reduced by 45%

increased fatty acids level ( J:201488 )

• at 4 weeks of age, hepatic synthesis of fatty acids from acetate is markedly increased 17-fold

• fatty acid species C18:0, C18:1n-9, C20:1n-9, C20:3n-9, and C22:4n-6 are significantly increased in liver; however, total amount of fatty acids is not significantly altered

• hepatic levels of diglycerides are increased 1.8-fold, but those of ceramides are not significantly increased

increased circulating free fatty acids level ( J:201488 )

• at 5 weeks of age, plasma free fatty acid levels are increased 3.1-fold

increased unsaturated fatty acids level ( J:201488 )

• at 4 weeks of age, the amounts of polyunsaturated fatty acids are increased in liver

increased liver triglyceride level ( J:201488 )

• at 4 weeks of age, hepatic triglyceride contents are increased 2-fold, indicating that neutral lipids stained with oil-red O in the liver are predominantly triglycerides

increased collagen level ( J:201488 )

• at 5 weeks of age, increased amounts of type 4 collagen are noted in liver

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

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

Contributing Projects: Mouse Genome Database (MGD), Gene Expression Database (GXD), Mouse Models of Human Cancer database (MMHCdb) (formerly Mouse Tumor Biology (MTB)), Gene Ontology (GO)
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