Cyclic AMP and fatty acids increase carnitine palmitoyltransferase I gene transcription in cultured fetal rat hepatocytes
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In the rat, the gene for liver mitochondrial carnitine palmitoyltransferase I (CPT I), though dormant prior to birth, is rapidly activated postnatally. We sought to elucidate which hormonal and/or nutritional factors might be responsible for this induction. In cultured hepatocytes from 20-day-old rat fetus, the concentration of CPT I mRNA, which initially was very low, increased dramatically in a dose-dependent manner after exposure of the cells to dibutyryl cAMP (Bt2cAMP). Similar results were obtained when long-chain fatty acids (LCFA), but not medium-chain fatty acids, were added to the culture medium. The effects of Bt2cAMP and LCFA were antagonized by insulin, also dose dependently. In contrast, CPT II gene expression, which was already high in fetal hepatocytes, was unaffected by any of the above manipulations. Bt2cAMP stimulated CPT I gene expression even when endogenous triacylglycerol breakdown was suppressed by lysosomotropic agents suggesting that the actions of cAMP and LCFA were distinct. Moreover, half-maximal concentrations of Bt2cAMP and linoleate produced an additive effect CPT I mRNA accumulation. While linoleate and Bt2cAMP stimulated CPT I gene transcription by twofold and fourfold, respectively, the fatty acid also increased the half-life of CPT I mRNA (50%). When hepatocytes were cultured in the presence of 2-bromopalmitate, (which is readily converted by cells into its non-metabolizable CoA ester) CPT I mRNA accumulation was higher than that observed with oleate or linoleate. Similarly, the CPT I inhibitor, tetradecylglycidate, which at a concentration of 20 microM did not itself influence the CPT I mRNA level, enhanced the stimulatory effect of linoleate. The implication is that induction of the CPT I message by LCFA does not require mitochondrial metabolism of these substrates; however, formation of their CoA esters is a necessary step. Unlike linoleate, the peroxisome proliferator, clofibrate, increased both CPT I and CPT II mRNA levels and neither effect was offset by insulin. It thus appears that the mechanism of action of LCFA differs from that utilized by clofibrate, which presumably works through the peroxisome proliferator activated receptor. We conclude that the rapid increase in hepatic CPT I mRNA level that accompanies the fetal to neonatal transition in the rat is triggered by the reciprocal change in circulating insulin and LCFA concentrations, coupled with elevation of the liver content of cAMP.
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Sensing of free fatty acid availability within the cell primarily occurs through peroxisome proliferator-activated receptors, which function as fatty acid-activated transcription factors that drive the expression of CPT1.
“Sensing of free fatty acid availability within the cell primarily occurs through peroxisome proliferator–activated receptors, which function as fatty acid–activated transcription factors that drive the expression of CPT1 (64, 65).”
From Regulation and function of the mammalian tricarboxylic acid cycle (2023) · cites this paper as [64]
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“Sensing of free fatty acid availability within the cell primarily occurs through peroxisome proliferator–activated receptors, which function as fatty acid–activated transcription factors that drive the expression of CPT1 (64, 65).”
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- Authors
- Chatelain, F., Kohl, C., Esser, V., Mcgarry, J. D., Girard, J., & Pegorier, J.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- The University of Texas Southwestern Medical Center (US)
- ORCID
- Esser, Victoria
- Venue
- European Journal of Biochemistry
- Publisher
- Wiley
- Published
- 1996-02
- Volume
- 235
- Issue
- 3
- Pages
- 789-798
- ISSN
- 0014-2956 (ISSN-L)
- 1432-1033
- OpenAlex
- W2070973234
- Cited by
- 123
- References
- 60
- Citations by year
- 2025: 1 · 2023: 3 · 2022: 1 · 2020: 1 · 2019: 2 · 2018: 3 · 2017: 3 · 2016: 2 · 2015: 3 · 2014: 1 · 2013: 1 · 2012: 3
- FWCI
- 7.53
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- European Journal of Biochemistry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 18573)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Keywords
- carnitine palmitoyltransferase 1, dibutyryl cyclic AMP, long-chain fatty acids, linoleate, insulin, fetal to adult transition, peroxisome proliferator-activated receptors, clofibrate
- MeSH terms
- Animals, Carnitine O-Palmitoyltransferase, Cells, Cultured, Clofibrate, Bucladesine, Fatty Acids, Female, Fetus, Isoenzymes, Mitochondria, Liver, RNA, Messenger, Transcription, Genetic, Rats, Wistar, Rats
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