Journal
JOURNAL OF LIPID RESEARCH
Volume 53, Issue 1, Pages 77-86Publisher
ELSEVIER
DOI: 10.1194/jlr.M021220
Keywords
protein farnesyltransferase; protein geranylgeranyltransferase; hyperbilirubinemia; hepatic steatosis; prelamin A; actin stress fibers
Categories
Funding
- National Institutes of Health [HL-76839, CA-099506-07, HL-086683, HL-089781]
- Ellison Medical Foundation
- March of Dimes [6-FY2007-1012]
- American Heart Association, Western States Affiliate [0865262F]
- UCLA [2 T32 HL069766:06]
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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-specifi c 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.-Yang, S. H., S.Y. Chang, Y. Tu, G. W. Lawson, M.O. Bergo, L. G. Fong, and S. G. Young. Severe hepatocellular disease in mice lacking one or both CaaX prenyltransferases. J. Lipid Res. 2012. 53: 77-86.
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