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Gene expression profiling in livers of mice after acute inhibition of beta-oxidation.
Genomics. 2007 Dec; 90(6):680-9.G

Abstract

Inborn errors of mitochondrial beta-oxidation cause ectopic fat accumulation, particularly in the liver. Fatty liver is associated with insulin resistance and predisposes to hepatic fibrosis. The factors underlying the pathophysiological consequences of hepatic fat accumulation have remained poorly defined. Gene expression profiling in a model of acute fatty liver disease induced by blocking long-chain fatty acid beta-oxidation was performed to study the early effects of steatosis on the transcriptome. Tetradecylglycidic acid (TDGA) was used to irreversibly inhibit carnitine palmitoyltransferase 1, a key enzyme in the control of mitochondrial beta-oxidation. TDGA treatment induced massive microvesicular hepatic steatosis within a 12-h time frame in male C57BL6/J mice. Increased hepatic long-chain acyl-CoA content, particularly of C16:0, C16:1 and C18:1, was associated with profound effects on the transcriptome as revealed by unbiased gene expression profiling and quantitative real-time PCR. The results indicate drastic changes in the expression of genes encoding proteins involved in lipid, carbohydrate, and amino acid metabolism. Pathway analysis identified transcription factors and coregulators such as hepatocyte nuclear factor 4 (HNF4), peroxisome proliferator-activated receptor-alpha (PPAR-alpha), and PPAR gamma coactivator 1alpha (PGC-1alpha) as key players in these metabolic adaptations. Apoptotic and profibrotic responses were also affected. Surprisingly, a strong reduction in the expression of genes involved in hepatic bile salt metabolism and transport was observed. Therefore, this transcriptome analysis opens new avenues for research.

Authors+Show Affiliations

Center for Liver, Digestive, and Metabolic Diseases, Laboratory of Pediatrics, University Medical Center Groningen, University of Groningen, CMCV, Groningen, The Netherlands.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17933490

Citation

van der Leij, Feike R., et al. "Gene Expression Profiling in Livers of Mice After Acute Inhibition of Beta-oxidation." Genomics, vol. 90, no. 6, 2007, pp. 680-9.
van der Leij FR, Bloks VW, Grefhorst A, et al. Gene expression profiling in livers of mice after acute inhibition of beta-oxidation. Genomics. 2007;90(6):680-9.
van der Leij, F. R., Bloks, V. W., Grefhorst, A., Hoekstra, J., Gerding, A., Kooi, K., Gerbens, F., te Meerman, G., & Kuipers, F. (2007). Gene expression profiling in livers of mice after acute inhibition of beta-oxidation. Genomics, 90(6), 680-9.
van der Leij FR, et al. Gene Expression Profiling in Livers of Mice After Acute Inhibition of Beta-oxidation. Genomics. 2007;90(6):680-9. PubMed PMID: 17933490.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Gene expression profiling in livers of mice after acute inhibition of beta-oxidation. AU - van der Leij,Feike R, AU - Bloks,Vincent W, AU - Grefhorst,Aldo, AU - Hoekstra,Jildou, AU - Gerding,Albert, AU - Kooi,Krista, AU - Gerbens,Frans, AU - te Meerman,Gerard, AU - Kuipers,Folkert, Y1 - 2007/10/22/ PY - 2007/05/14/received PY - 2007/08/06/revised PY - 2007/08/06/accepted PY - 2007/10/16/pubmed PY - 2008/2/12/medline PY - 2007/10/16/entrez SP - 680 EP - 9 JF - Genomics JO - Genomics VL - 90 IS - 6 N2 - Inborn errors of mitochondrial beta-oxidation cause ectopic fat accumulation, particularly in the liver. Fatty liver is associated with insulin resistance and predisposes to hepatic fibrosis. The factors underlying the pathophysiological consequences of hepatic fat accumulation have remained poorly defined. Gene expression profiling in a model of acute fatty liver disease induced by blocking long-chain fatty acid beta-oxidation was performed to study the early effects of steatosis on the transcriptome. Tetradecylglycidic acid (TDGA) was used to irreversibly inhibit carnitine palmitoyltransferase 1, a key enzyme in the control of mitochondrial beta-oxidation. TDGA treatment induced massive microvesicular hepatic steatosis within a 12-h time frame in male C57BL6/J mice. Increased hepatic long-chain acyl-CoA content, particularly of C16:0, C16:1 and C18:1, was associated with profound effects on the transcriptome as revealed by unbiased gene expression profiling and quantitative real-time PCR. The results indicate drastic changes in the expression of genes encoding proteins involved in lipid, carbohydrate, and amino acid metabolism. Pathway analysis identified transcription factors and coregulators such as hepatocyte nuclear factor 4 (HNF4), peroxisome proliferator-activated receptor-alpha (PPAR-alpha), and PPAR gamma coactivator 1alpha (PGC-1alpha) as key players in these metabolic adaptations. Apoptotic and profibrotic responses were also affected. Surprisingly, a strong reduction in the expression of genes involved in hepatic bile salt metabolism and transport was observed. Therefore, this transcriptome analysis opens new avenues for research. SN - 0888-7543 UR - https://www.unboundmedicine.com/medline/citation/17933490/Gene_expression_profiling_in_livers_of_mice_after_acute_inhibition_of_beta_oxidation_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0888-7543(07)00204-2 DB - PRIME DP - Unbound Medicine ER -