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Severe hepatocellular disease in mice lacking one or both CaaX prenyltransferases[S]
- Source :
- Journal of Lipid Research, Vol 53, Iss 1, Pp 77-86 (2012)
- Publication Year :
- 2012
- Publisher :
- Elsevier, 2012.
-
Abstract
- Protein farnesyltransferase (FTase) and protein geranylgeranyltransferase-I (GGTase-I) add 15- or 20-carbon lipids, respectively, to proteins that terminate with a CaaX motif. These posttranslational modifications of proteins with lipids promote protein interactions with membrane surfaces in cells, but the in vivo importance of the CaaX prenyltransferases and the protein lipidation reactions they catalyze remain incompletely defined. One study concluded that a deficiency of FTase was inconsequential in adult mice and led to little or no tissue pathology. To assess the physiologic importance of the CaaX prenyltransferases, we used conditional knockout alleles and an albumin–Cre transgene to produce mice lacking FTase, GGTase-I, or both enzymes in hepatocytes. The hepatocyte-specific FTase knockout mice survived but exhibited hepatocellular disease and elevated transaminases. Mice lacking GGTase-I not only had elevated transaminases but also had dilated bile cannaliculi, hyperbilirubinemia, hepatosplenomegaly, and reduced survival. Of note, GGTase-I–deficient hepatocytes had a rounded shape and markedly reduced numbers of actin stress fibers. Hepatocyte-specific FTase/GGTase-I double-knockout mice closely resembled mice lacking GGTase-I alone, but the disease was slightly more severe. Our studies refute the notion that FTase is dispensable and demonstrate that GGTase-I is crucial for the vitality of hepatocytes.
- Subjects :
- hyperbilirubinemia
Farnesyltransferase
Transgene
Protein Prenylation
QD415-436
Protein lipidation
Biochemistry
Mice
Endocrinology
Conditional gene knockout
Animals
Farnesyltranstransferase
protein farnesyltransferase
Actin
Research Articles
Mice, Knockout
prelamin A
Alkyl and Aryl Transferases
actin stress fibers
biology
Liver Diseases
hepatic steatosis
Cell Biology
Dimethylallyltranstransferase
Cell biology
Liver
Knockout mouse
biology.protein
Hepatocytes
Protein prenylation
protein geranylgeranyltransferase
Subjects
Details
- Language :
- English
- ISSN :
- 00222275
- Volume :
- 53
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Journal of Lipid Research
- Accession number :
- edsair.doi.dedup.....9590f21bfe57df7c800337f6911a9763