Hepatocyte-specific expression of Cre recombinase

Kellendonk, Christoph; Opherk, Christian; Anlag, Katrin; Schütz, Günther; Tronche, François

doi:10.1002/(sici)1526-968x(200002)26:2<151::aid-gene17>3.0.co;2-e

Cited by 227 publications

(224 citation statements)

References 10 publications

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“…To analyze the function of EGFR during perinatal and early postnatal liver development, EGFR was inactivated tissue specifically in hepatocytes by using Alfp-cre transgenic mice, in which the cre recombinase is under the control of the liver-specific albumin promoter and albumin and ␣-feto-protein enhancers (26). EGFR f/f Alfp-cre (EGFR ⌬hep ) transgenic mice were born at Mendelian frequency and displayed reduced body weight, which was evident from the third postnatal week and persisted throughout adulthood ( Fig.…”

Section: Deletion Of Egfr In the Livermentioning

confidence: 99%

The EGF receptor is required for efficient liver regeneration

Natarajan

Wagner²,

Sibilia³

2007

Proc. Natl. Acad. Sci. U.S.A.

273

242

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Mice lacking the EGF receptor (EGFR) die between midgestation and postnatal day 20 with various defects in neural and epithelial organs. Here, we generated mice carrying a floxed EGFR allele to inactivate the EGFR in fetal and adult liver. Perinatal deletion of EGFR in hepatocytes resulted in decreased body weight, whereas deletion in the adult liver did not affect body mass. Although liver function was not affected, after partial hepatectomy mice lacking EGFR in the liver showed increased mortality accompanied by increased levels of serum transaminases indicating liver damage. Liver regeneration was delayed in the mutants because of reduced hepatocyte proliferation. Analysis of cell cycle progression in EGFR-deficient livers indicated a defective G 1 –S phase entry with delayed transcriptional activation and reduced protein expression of cyclin D1 followed by reduced cdk2 and cdk1 expression. Impaired liver regeneration was accompanied by compensatory up-regulation of TNFα in the serum and prolonged activation of c-Jun. Moreover, p38α and NF-κB activation was reduced in regenerating mutant livers, indicating an impaired stress response after hepatectomy. Our studies demonstrate that EGFR is a critical regulator of hepatocyte proliferation in the initial phases of liver regeneration.

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Section: Deletion Of Egfr In the Livermentioning

confidence: 99%

The EGF receptor is required for efficient liver regeneration

Natarajan

Wagner²,

Sibilia³

2007

Proc. Natl. Acad. Sci. U.S.A.

273

242

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“…To further define the role of NF-B activation in the regulation of metabolic and inflammatory pathways in the liver, we used mice lacking NEMO specifically in liver parenchymal cells (NEMO L-KO ), generated by crossing NEMO FL/FL mice (14) with ALFP-Cre mice (15). Southern blot and immunoblot analysis revealed efficient recombination of the loxP-flanked NEMO allele exclusively in hepatocytes of NEMO L-KO mice without altering expression of hepatic IKK1 and IKK2 [supporting information (SI) Fig.…”

Section: Resultsmentioning

confidence: 99%

Hepatic NF-κB essential modulator deficiency prevents obesity-induced insulin resistance but synergizes with high-fat feeding in tumorigenesis

Wunderlich

Luedde

Singer

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

103

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Development of obesity-associated insulin resistance and diabetes mellitus type 2 has been linked to activation of proinflammatory pathways in the liver, leading to impaired insulin signal transduction. To further define the role of hepatic NF-B activation in this process, we have analyzed glucose metabolism in mice with liver-specific inactivation of the NF-B essential modulator gene (NEMO L-KO mice) exposed to a high-fat diet (HFD). These animals are protected from the development of obesity-associated insulin resistance, highlighting the importance of hepatic NF-B activation in this context. However, hepatic NEMO deficiency synergizes with HFD in the development of liver steatosis as a consequence of decreased peroxisome proliferator-activated receptor (PPAR-␣) and increased PPAR-␥ expression. Steatosis interacts with increased inflammation, causing elevated apoptosis in the livers of these mice under HFD. These changes result in liver tumorigenesis of NEMO L-KO mice under normal diet, a process that is largely aggravated when these mice are exposed to HFD. These data directly demonstrate the interaction of hepatic inflammation, dietary composition, and metabolism in the development of liver tumorigenesis.insulin sensitivity ͉ spontaneous hepatic carcinoma ͉ steatosis ͉ hepatic NEMO deficiency E xcessive weight gain is associated with a chronic inflammatory state in white adipose tissue that releases proinflammatory cytokines such as TNF and IL-6 into circulation (1). While adipocytes have also been demonstrated to exhibit increased expression of proinflammatory cytokines in obesity (1), more recent studies have revealed that increased macrophage infiltration of white adipose tissue contributes to the proinflammatory state under conditions of obesity (2). These cytokines inhibit insulin action in classical insulin target tissues such as skeletal muscle, liver, and adipose cells, thereby resulting in alterations of glucose homeostasis (3). More recently, TNFstimulated activation of the JNK and NF-B signaling pathways has been demonstrated to inhibit insulin action in a tissuespecific manner (3-5). With respect to NF-B signaling, TNF binding induces activation of the IKK-1 and -2 kinases that are released from a multiproteincomplex containing the regulatory subunit NF-B essential modulator (NEMO), thereby mediating phosphorylation and subsequent proteasomal degradation of I-Bs liberating the transcription factor NF-B.In addition to predisposing to insulin resistance and diabetes, obesity also represents a major risk factor for the development of the malignant neoplasias (4-8). It has been clearly demonstrated that metabolic syndrome is a key factor leading to sequential development of hepatic steatosis, steatohepatitis, hepatic fibrosis, cirrhosis, and finally increased frequency of hepatocellular carcinoma (HCC) (10). Thus, steatohepatitis represents a key feature of this particular tumor entity. Recent work has also demonstrated that the NF-B signaling pathway plays a crucial role in the development of malign...

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“…The following mouse lines were used in this study: AlfpCre, 31 NEMO floxed, 10 FADD floxed, 32 Tnf À / À , 23 33 TRAIL-R floxed, 34 Fas floxed 35 and Rag1 À / À . 36 All mice were maintained in C57BL/6 background.…”

Section: Methodsmentioning

confidence: 99%

Death receptor-independent FADD signalling triggers hepatitis and hepatocellular carcinoma in mice with liver parenchymal cell-specific NEMO knockout

et al. 2014

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Hepatocellular carcinoma (HCC) usually develops in the context of chronic hepatitis triggered by viruses or toxic substances causing hepatocyte death, inflammation and compensatory proliferation of liver cells. Death receptors of the TNFR superfamily regulate cell death and inflammation and are implicated in liver disease and cancer. Liver parenchymal cell-specific ablation of NEMO/IKKc, a subunit of the IjB kinase (IKK) complex that is essential for the activation of canonical NF-jB signalling, sensitized hepatocytes to apoptosis and caused the spontaneous development of chronic hepatitis and HCC in mice. Here we show that hepatitis and HCC development in NEMO LPC-KO mice is triggered by death receptor-independent FADD-mediated hepatocyte apoptosis. TNF deficiency in all cells or conditional LPC-specific ablation of TNFR1, Fas or TRAIL-R did not prevent hepatocyte apoptosis, hepatitis and HCC development in NEMO LPC-KO mice. To address potential functional redundancies between death receptors we generated and analysed NEMO LPC-KO mice with combined LPC-specific deficiency of TNFR1, Fas and TRAIL-R and found that also simultaneous lack of all three death receptors did not prevent hepatocyte apoptosis, chronic hepatitis and HCC development. However, LPC-specific combined deficiency in TNFR1, Fas and TRAIL-R protected the NEMOdeficient liver from LPS-induced liver failure, showing that different mechanisms trigger spontaneous and LPS-induced hepatocyte apoptosis in NEMO LPC-KO mice. In addition, NK cell depletion did not prevent liver damage and hepatitis. Moreover, NEMO LPC-KO mice crossed into a RAG-1-deficient genetic background-developed hepatitis and HCC. Collectively, these results show that the spontaneous development of hepatocyte apoptosis, chronic hepatitis and HCC in NEMO LPC-KO mice occurs independently of death receptor signalling, NK cells and B and T lymphocytes, arguing against an immunological trigger as the critical stimulus driving hepatocarcinogenesis in this model.

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Hepatocyte-specific expression of Cre recombinase

Cited by 227 publications

References 10 publications

The EGF receptor is required for efficient liver regeneration

The EGF receptor is required for efficient liver regeneration

Hepatic NF-κB essential modulator deficiency prevents obesity-induced insulin resistance but synergizes with high-fat feeding in tumorigenesis

Death receptor-independent FADD signalling triggers hepatitis and hepatocellular carcinoma in mice with liver parenchymal cell-specific NEMO knockout

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