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J. Biol. Chem., Vol. 279, Issue 43, 44740-44748, October 22, 2004

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Disruption of Hepatic C/EBP Results in Impaired Glucose Tolerance and Age-dependent Hepatosteatosis^*

Yusuke Inoue, Junko Inoue, Gilles Lambert¶, Sun Hee Yim, and Frank J. Gonzalez||

From the Laboratory of Metabolism, Center for Cancer Research, NCI, National Institutes of Health, Bethesda, Maryland 20892 and ^¶INSERM U539, Nantes 44035, France

C/EBP is highly expressed in liver and regulates many genes that are preferentially expressed in liver. Because C/EBP-null mice die soon after birth, it is impossible to analyze the function of C/EBP in the adult with this model. To address the function of C/EBP in adult hepatocytes, liver-specific C/EBP-null mice were produced using a floxed C/EBP allele and the albumin-Cre transgene. Unlike whole body C/EBP-null mice, mice lacking hepatic C/EBP expression did not exhibit hypoglycemia, nor did they show reduced hepatic glycogen in adult. Expression of liver glycogen synthase, phosphoenolpyruvate carboxykinase, and glucose-6-phosphatase remained at normal levels. However, these mice exhibited impaired glucose tolerance due in part to reduced expression of hepatic glucokinase, and hyperammonemia from reduced expression of hepatic carbamoyl phosphate synthase-I. These mice also had reduced serum cholesterol and steatotic livers that was exacerbated with aging. This phenotype could be explained by increased expression of hepatic lipoprotein lipase and reduced expression of microsomal triglyceride transfer protein, apolipoproteins B100, and A-IV. These data demonstrate that hepatic C/EBP is critical for ammonia detoxification and glucose and lipid homeostasis in adult mice.

Received for publication, May 10, 2004 , and in revised form, July 22, 2004.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Both authors contributed equally to this work.

^|| To whom correspondence should be addressed: Bldg. 37, Rm. 3106, National Institutes of Health, Bethesda, MD 20892. Tel.: 301-496-9067; Fax: 301-496-8419; E-mail: fjgonz{at}helix.nih.gov.

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