Evidence for triacylglycerol synthesis in the lumen of microsomes via a lipolysis-esterification pathway involving carnitine acyltransferases.

Abo-Hashema, Khaled A.H.; Cake, Max H.; Power, Glen W.; Clarke, Doug

doi:10.1016/s0021-9258(19)62272-6

Cited by 5 publications

(5 citation statements)

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“…Typically, acylcarnitines are delivered into mitochondrial matrix by carnitine-acylcarnitine translocase, where they are rethioesterified back to acyl CoA by CPT-II prior to utilization in energy-producing fatty acid β oxidative pathways. Recent studies have also suggested involvement of acylcarnitines in the transport of acyl moieties into peroxisomes or ER (41,(51)(52)(53), which indicate the potential complexity of roles of acylcarnitines in intracellular fatty acid trafficking. Once acylcarnitines are synthesized, they can be hydrolyzed back to FFAs and carnitine and diffuse to different intracellular organelles or be transported by specific transporters for fatty acid oxidation or TAG synthesis (10,51).…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies have also suggested involvement of acylcarnitines in the transport of acyl moieties into peroxisomes or ER (41,(51)(52)(53), which indicate the potential complexity of roles of acylcarnitines in intracellular fatty acid trafficking. Once acylcarnitines are synthesized, they can be hydrolyzed back to FFAs and carnitine and diffuse to different intracellular organelles or be transported by specific transporters for fatty acid oxidation or TAG synthesis (10,51). Because measured acylcarnitine hydrolase activity does not change during diabetes and consumption of acylcarnitines by FAO is increased in diabetic hearts, it seems likely that the accumulation of acylcarnitine is likely due to an increase in the acylcarnitine synthetic rates, which cannot be accommodated by accelerated flux through oxidative pathways in diabetic myocardium.…”

Section: Discussionmentioning

confidence: 99%

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Accumulation of Long-Chain Acylcarnitine and 3-Hydroxy Acylcarnitine Molecular Species in Diabetic Myocardium: Identification of Alterations in Mitochondrial Fatty Acid Processing in Diabetic Myocardium by Shotgun Lipidomics

et al. 2005

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Diabetic cardiomyopathy is the result of maladaptive changes in energy homeostasis. However, the biochemical mechanisms underlying dysfunctional lipid metabolism in diabetic myocardium are incompletely understood. Herein, we exploit shotgun lipidomics to demonstrate a 4-fold increase in acylcarnitines in diabetic myocardium, which was reversible upon insulin treatment. Analysis of acylcarnitine molecular species in myocardium unexpectedly identified acylcarnitine molecular species containing a mass shift of 16 amu in comparison to the anticipated molecular species. Synthesis of 3-hydroxy acylcarnitine identified the natural products as the 3-hydroxylated acylcarnitines through comparisons of diagnostic fragmentation patterns of synthetic and naturally occurring constituents using tandem mass spectrometry. Diabetes induced an increase of both calcium-independent phospholipase A(2) (iPLA(2)) mRNA and iPLA(2) activity in rat myocardium. Cardiac ischemia in myocardium genetically engineered to overexpress iPLA(2) dramatically increased the amount of acylcarnitine present in myocardium. Moreover, mechanism-based inactivation of iPLA(2) in either wild-type or transgenic myocardium ablated a substantial portion of the acylcarnitine increase. Collectively, these results identify discrete insulin remediable abnormalities in mitochondrial fatty acid processing in diabetic myocardium and identify iPLA(2) as an important enzymatic contributor to the pool of fatty acids that can be used for acylcarnitine synthesis and energy production in myocardium.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Accumulation of Long-Chain Acylcarnitine and 3-Hydroxy Acylcarnitine Molecular Species in Diabetic Myocardium: Identification of Alterations in Mitochondrial Fatty Acid Processing in Diabetic Myocardium by Shotgun Lipidomics

et al. 2005

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“…Following the lipolysis of stored TAG, lipolytic products are re-synthesized to form TAG at the ER, where the TAG may be utilized for lipoprotein assembly [11,12]. The final stage of TAG synthesis is catalysed by DGAT (diacylglycerol acyltransferase).…”

Section: Introductionmentioning

confidence: 99%

Regulation of the enzymes of hepatic microsomal triacylglycerol lipolysis and re-esterification by the glucocorticoid dexamethasone

Dolinsky

Douglas

Lehner

et al. 2004

Biochemical Journal

113

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Hepatic VLDL (very-low-density lipoprotein) assembly is a complex process that is largely regulated by the provision of lipid for apolipoprotein B assembly. Intracellular stored TAG (triacylglycerol) undergoes an initial lipolysis followed by re-esterification of the lipolytic products to form TAG prior to their incorporation into a VLDL particle. TGH (TAG hydrolase) is a lipase that hydrolyses intracellular TAG within the hepatocyte. We have utilized both dexamethasone-injected mouse and primary hepatocyte models to address whether stimulation of TAG biosynthesis by the synthetic glucocorticoid, dexamethasone, altered hepatic lipolysis and re-esterification and the provision of stored TAG for lipoprotein secretion. Dexamethasone treatment resulted in decreased TGH expression, primarily due to a dexamethasone-induced decrease in TGH mRNA stability. The expression and activities of diacylglycerol acyltransferases 1 and 2 were stimulated by dexamethasone. The combination of reduced intracellular TAG lipolysis and increased TAG biosynthesis contributed to the accumulation of TAG within the livers of dexamethasone-injected mice. The rate of hepatic TAG secretion in dexamethasonetreated mice was maintained at similar levels as in control mice. Our data demonstrate that stimulation of de novo TAG synthesis by dexamethasone increased the proportion of secreted TAG that was derived from de novo sources, while the utilization of stored TAG for secretion was reduced. The results show that, during markedly increased TAG synthesis, some TAGs are diverted from the cytosolic storage pool and are utilized directly for VLDL assembly within the endoplasmic reticulum lumen.

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“…Various isoforms of CPT1 are also part of the peroxisomal and microsomal acyltransferase system, the latter appearing to influence whether triglycerides accumulate in the cytosol or whether they are exported via lipoproteins (very low-density lipoproteins; VLDLs) to peripheral tissues (Jin et al 1992; Abo-Hashema et al 1999; Broadway et al 1999).…”

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confidence: 99%

Dietary L-carnitine Stimulates Carnitine Acyltransferases in the Liver of Aged Rats

Karlic

Lohninger

Koeck

et al. 2002

J Histochem Cytochem.

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S U M M A R YAging affects oxidative metabolism in liver and other tissues. Carnitine acyltransferases are key enzymes of this process in mitochondria. As previously shown, the rate of transcription and activity of carnitine palmitoyltransferase CPT1 are also related to carnitine levels. In this study we compared the effect of dietary L -carnitine (100 mg L -carnitine/ kg body weight/day over 3 months) on liver enzymes of aged rats (months 21-24) to adult animals (months 6-9) and age-related controls for both groups. The transcription rate of CPT1, CPT2, and carnitine acetyltransferase (CRAT) was determined by quantitative reverse transcription real-time PCR (RTQPCR) and compared to the activity of the CPT1A enzyme. The results showed that the transcription rates of CPT1, CPT2, and CRAT were similar in aged and adult control animals. Carnitine-fed old rats had a significant ( p Ͻ 0.05) 8-12-fold higher mean transcription rate of CPT1 and CRAT compared to aged controls, adult carnitine-fed animals, and adult controls, whereas the transcription rate of CPT2 was stimulated 2-3-fold in carnitine-fed animals of both age groups. With regard to the enzymatic activity of CPT1 there was a 1.5-fold increase in the old carnitine group compared to all other groups. RNA in situ hybridization also indicated an enhanced expression of CPT1A in hepatocytes from L -carnitine-supplemented animals. These results suggest that L -carnitine stimulates transcription of CPT1, CPT2, and CRAT as well as the enzyme activity of CPT1 in the livers of aged rats.

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Evidence for triacylglycerol synthesis in the lumen of microsomes via a lipolysis-esterification pathway involving carnitine acyltransferases.

Cited by 5 publications

References 0 publications

Accumulation of Long-Chain Acylcarnitine and 3-Hydroxy Acylcarnitine Molecular Species in Diabetic Myocardium: Identification of Alterations in Mitochondrial Fatty Acid Processing in Diabetic Myocardium by Shotgun Lipidomics

Accumulation of Long-Chain Acylcarnitine and 3-Hydroxy Acylcarnitine Molecular Species in Diabetic Myocardium: Identification of Alterations in Mitochondrial Fatty Acid Processing in Diabetic Myocardium by Shotgun Lipidomics

Regulation of the enzymes of hepatic microsomal triacylglycerol lipolysis and re-esterification by the glucocorticoid dexamethasone

Dietary L-carnitine Stimulates Carnitine Acyltransferases in the Liver of Aged Rats

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