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Effects of thyroidectomy and starvation on the activity and properties of hepatic carnitine palmitoyltransferase.

ABSTRACT: 1. Hepatic carnitine palmitoyltransferase activity was measured over a range of concentrations of palmitoyl-CoA and in the presence of several concentrations of the inhibitor malonyl-CoA. These measurements were made in mitochondria obtained from the livers of fed and starved (24 h) normal rats and of fed and starved thyroidectomized rats. 2. In the fed state thyroidectomy substantially decreased overt carnitine palmitoyltransferase activity and also decreased both the Hill coefficient and the s0.5 when palmitoyl-CoA concentration was varied as substrate. Thyroidectomy did not appreciably alter the inhibitory effect of malonyl-CoA on the enzyme. 3. Starvation increased overt carnitine palmitoyltransferase activity in both the fed and the thyroidectomized state. In percentage terms this response to starvation was substantially greater after thyroidectomy. In both the hypothyroid and normal states starvation decreased sensitivity to inhibition by malonyl-CoA.

SUBMITTER: Saggerson ED

PROVIDER: S-EPMC1154016 | biostudies-other | 1982 Dec

REPOSITORIES: biostudies-other

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Hepatic mitochondrial inner membrane properties and carnitine palmitoyltransferase A and B. Effect of diabetes and starvation.

Project description:Intact mitochondria and inverted submitochondrial vesicles were prepared from the liver of fed, starved (48 h) and streptozotocin-diabetic rats in order to characterize carnitine palmitoyltransferase kinetics and malonyl-CoA sensitivity in situ. In intact mitochondria, both starved and diabetic rats exhibited increased Vmax., increased Km for palmitoyl-CoA, and decreased sensitivity to malonyl-CoA inhibition. Inverted submitochondrial vesicles also showed increased Vmax. with starvation and diabetes, with no change in Km for either palmitoyl-CoA or carnitine. Inverted vesicles were uniformly less sensitive to malonyl-CoA regardless of treatment, and diabetes resulted in a further decrease in sensitivity. In part, differences in the response of carnitine palmitoyltransferase to starvation and diabetes may reside in differences in the membrane environment, as observed with Arrhenius plots, and the relation of enzyme activity and membrane fluidity. In all cases, whether rats were fed, starved or diabetic, and whether intact or inverted vesicles were examined, increasing membrane fluidity was associated with increasing activity. Malonyl-CoA was found to produce a decrease in intact mitochondrial membrane fluidity in the fed state, particularly at pH 7.0 or less. No effect was observed in intact mitochondria from starved or diabetic rats, or in inverted vesicles from any of the treatment groups. Through its effect on membrane fluidity, malonyl-CoA could regulate carnitine palmitoyltransferase activity on both surfaces of the inner membrane through an interaction with only the outer surface.

| S-EPMC1152900 | biostudies-other

Response to starvation of hepatic carnitine palmitoyltransferase activity and its regulation by malonyl-CoA. Sex differences and effects of pregnancy.

Project description:1. Hepatic carnitine palmitoyltransferase activity was measured over a range of concentrations of palmitoyl-CoA and in the presence of several concentrations of the inhibitor malonyl-CoA. These measurements were made in mitochondria obtained from the livers of fed and starved (24 h) virgin female and fed and starved pregnant rats. 2. In the fed state overt carnitine palmitoyltransferase activity was significantly lower in virgin females than in age-matched male rats. 3. Starvation increased overt carnitine palmitoyltransferase activity in both virgin and pregnant females. This increase was larger than in the male and was greater in pregnant than in virgin females. 4. In the fed state pregnancy had no effect on the Hill coefficient or the [S]0.5 when palmitoyl-CoA was varied as substrate. Pregnancy did not alter the sensitivity of the enzyme to inhibition by malonyl-CoA. 5. Starvation decreased the sensitivity of the enzyme to malonyl-CoA. The change in sensitivity was similar in male, virgin female and pregnant rats. 6. The possible relevance of these findings to known sex differences and changes with pregnancy in hepatic fatty acid oxidation and esterification are discussed.

| S-EPMC1154017 | biostudies-other

Carnitine Palmitoyltransferase 1A Has a Lysine Succinyltransferase Activity.

Project description:Lysine succinylation was recently identified as a post-translational modification in cells. However, the molecular mechanism underlying lysine succinylation remains unclear. Here, we show that carnitine palmitoyltransferase 1A (CPT1A) has lysine succinyltransferase (LSTase) activity in vivo and in vitro. Using a stable isotope labeling by amino acid in cell culture (SILAC)-based proteomics approach, we found that 101 proteins were more succinylated in cells expressing wild-type (WT) CPT1A compared with vector control cells. One of the most heavily succinylated proteins in this analysis was enolase 1. We found that CPT1A WT succinylated enolase 1 and reduced enolase enzymatic activity in cells and in vitro. Importantly, mutation of CPT1A Gly710 (G710E) selectively inactivated carnitine palmitoyltransferase (CPTase) activity but not the LSTase activity that decreased enolase activity in cells and promoted cell proliferation under glutamine depletion. These findings suggest that CPT1A acts as an LSTase that can regulate enzymatic activity of a substrate protein and metabolism independent of its classical CPTase activity.

| S-EPMC5826573 | biostudies-literature

Cycloheximide blocks changes in rat liver carnitine palmitoyltransferase 1 activity in starvation.

Project description:Starvation (24h) increased the maximum activity of carnitine palmitoyltransferase 1 in rat liver and increased the concentration of malonyl-CoA required to cause 50% inhibition of the enzyme (I50). Re-feeding (24h) with a standard cube diet or a high-carbohydrate diet reversed both of these changes, whereas re-feeding with a high-fat diet did not. Administration of cycloheximide (200 micrograms/100 g body wt.) blocked the increases in carnitine palmitoyltransferase 1 activity and I50 on starvation. It is suggested that increase in carnitine palmitoyltransferase 1 activity in starvation may involve synthesis of new enzyme.

| S-EPMC1144414 | biostudies-other

Hepatic mitochondrial inner-membrane properties, beta-oxidation and carnitine palmitoyltransferases A and B. Effects of genetic obesity and starvation.

Project description:Hepatic mitochondrial carnitine palmitoyltransferase (CPT) properties, beta-oxidation of palmitoyl-CoA and membrane polarization were measured in lean and obese Zucker rats. The Vmax. of the 'outer' carnitine palmitoyltransferase ('CPT-A') increased with starvation, with no change in the Km for either carnitine or palmitoyl-CoA. The Ki for malonyl-CoA increased with starvation in lean rats, but not in obese rats. The Vmax. of the 'inner' enzyme ('CPT-B'), as measured by using inverted submitochondrial vesicles, increased with starvation in obese rats only, with no change in the Km for either carnitine or palmitoyl-CoA. The Ki for malonyl-CoA was 2-5-fold higher in inverted vesicles than in intact mitochondria, and showed no alteration with starvation. The activities of both enzymes correlated positively with each other and with beta-oxidation, and inversely with membrane polarization. Malonyl-CoA had little effect on gross membrane fluidity in the Zucker rat, as reflected by diphenylhexatriene fluorescence polarization. The results indicate that both enzymes are related and respond similarly to alterations in membrane fluidity. Membrane fluidity may provide a mechanism for co-ordinated control of CPT activity on both sides of the mitochondrial inner membrane.

| S-EPMC1153043 | biostudies-other

Inhibition of carnitine palmitoyltransferase-1 activity alleviates insulin resistance in diet-induced obese mice.

Project description:Impaired skeletal muscle fatty acid oxidation has been suggested to contribute to insulin resistance and glucose intolerance. However, increasing muscle fatty acid oxidation may cause a reciprocal decrease in glucose oxidation, which might impair insulin sensitivity and glucose tolerance. We therefore investigated what effect inhibition of mitochondrial fatty acid uptake has on whole-body glucose tolerance and insulin sensitivity in obese insulin-resistant mice. C57BL/6 mice were fed a high-fat diet (60% calories from fat) for 12 weeks to develop insulin resistance. Subsequent treatment of mice for 4 weeks with the carnitine palmitoyltransferase-1 inhibitor, oxfenicine (150 mg/kg i.p. daily), resulted in improved whole-body glucose tolerance and insulin sensitivity. Exercise capacity was increased in oxfenicine-treated mice, which was accompanied by an increased respiratory exchange ratio. In the gastrocnemius muscle, oxfenicine increased pyruvate dehydrogenase activity, membrane GLUT4 content, and insulin-stimulated Akt phosphorylation. Intramyocellular levels of lipid intermediates, including ceramide, long-chain acyl CoA, and diacylglycerol, were also decreased. Our results demonstrate that inhibition of mitochondrial fatty acid uptake improves insulin sensitivity in diet-induced obese mice. This is associated with increased carbohydrate utilization and improved insulin signaling in the skeletal muscle, suggestive of an operating Randle Cycle in muscle.

| S-EPMC3581198 | biostudies-literature

Carnitine Palmitoyltransferase 1 Increases Lipolysis, UCP1 Protein Expression and Mitochondrial Activity in Brown Adipocytes.

Project description:The discovery of active brown adipose tissue (BAT) in adult humans and the fact that it is reduced in obese and diabetic patients have put a spotlight on this tissue as a key player in obesity-induced metabolic disorders. BAT regulates energy expenditure through thermogenesis; therefore, harnessing its thermogenic fat-burning power is an attractive therapeutic approach. We aimed to enhance BAT thermogenesis by increasing its fatty acid oxidation (FAO) rate. Thus, we expressed carnitine palmitoyltransferase 1AM (CPT1AM), a permanently active mutant form of CPT1A (the rate-limiting enzyme in FAO), in a rat brown adipocyte (rBA) cell line through adenoviral infection. We found that CPT1AM-expressing rBA have increased FAO, lipolysis, UCP1 protein levels and mitochondrial activity. Additionally, enhanced FAO reduced the palmitate-induced increase in triglyceride content and the expression of obese and inflammatory markers. Thus, CPT1AM-expressing rBA had enhanced fat-burning capacity and improved lipid-induced derangements. This indicates that CPT1AM-mediated increase in brown adipocytes FAO may be a new approach to the treatment of obesity-induced disorders.

| S-EPMC4954705 | biostudies-literature

Carnitine palmitoyltransferase II deficiency: successful anaplerotic diet therapy.

Project description:BackgroundCarnitine palmitoyltransferase II (CPT II) deficiency is an important cause of recurrent rhabdomyolysis in children and adults. Current treatment includes dietary fat restriction, with increased carbohydrate intake and exercise restriction to avoid muscle pain and rhabdomyolysis.MethodsCPT II enzyme assay, DNA mutation analysis, quantitative analysis of acylcarnitines in blood and cultured fibroblasts, urinary organic acids, the standardized 36-item Short-Form Health Status survey (SF-36) version 2, and bioelectric impedance for body fat composition. Diet treatment with triheptanoin at 30% to 35% of total daily caloric intake was used for all patients.ResultsSeven patients with CPT II deficiency were studied from 7 to 61 months on the triheptanoin (anaplerotic) diet. Five had previous episodes of rhabdomyolysis requiring hospitalizations and muscle pain on exertion prior to the diet (two younger patients had not had rhabdomyolysis). While on the diet, only two patients experienced mild muscle pain with exercise. During short periods of noncompliance, two patients experienced rhabdomyolysis with exercise. None experienced rhabdomyolysis or hospitalizations while on the diet. All patients returned to normal physical activities including strenuous sports. Exercise restriction was eliminated. Previously abnormal SF-36 physical composite scores returned to normal levels that persisted for the duration of the therapy in all five symptomatic patients.ConclusionsThe triheptanoin diet seems to be an effective therapy for adult-onset carnitine palmitoyltransferase II deficiency.

| S-EPMC2676979 | biostudies-literature

Carnitine palmitoyltransferase 1C contributes to progressive cellular senescence.

Project description:Stable transfection manipulation with antibiotic selection and passaging induces progressive cellular senescence phenotypes. However, the underlying mechanisms remain poorly understood. This study demonstrated that stable transfection of the empty vector induced PANC-1 cells into cellular senescence. Metabolomics revealed several acylcarnitines and their upstream regulatory gene, carnitine palmitoyltransferase 1C (CPT1C) involved in fatty acid β-oxidation in mitochondria, were strikingly decreased in senescent PANC-1 cells. Low CPT1C expression triggered mitochondrial dysfunction, inhibited telomere elongation, impaired cell survival under metabolic stress, and hindered the malignance and tumorigenesis of senescent cells. On the contrary, mitochondrial activity was restored by CPT1C gain-of-function in senescent vector PANC-1 cells. PPARα and TP53/CDKN1A, crucial signaling components in cellular senescence, were downregulated in senescent PANC-1 cells. This study identifies CPT1C as a key regulator of stable transfection-induced progressive PANC-1 cell senescence that inhibits mitochondrial function-associated metabolic reprogramming. These findings confirm the need to identify cell culture alterations after stable transfection, particularly when cells are used for metabolomics and mitochondria-associated studies, and suggest inhibition of CPT1C could be a promising target to intervene pancreatic tumorigenesis.

| S-EPMC7202531 | biostudies-literature

Cholestatic Jaundice Associated with Carnitine Palmitoyltransferase IA Deficiency.

Project description:Liver dysfunction usually accompanies metabolic decompensation in fatty acid oxidation disorders, including carnitine palmitoyltransferase (CPT) Ia deficiency. Typically, the liver is enlarged with raised plasma transaminase activities and steatosis on histological examination. In contrast, cholestatic jaundice is rare, having only been reported in long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency. We report a 3-year-old boy with CPT Ia deficiency who developed hepatomegaly and cholestatic jaundice following a viral illness. No cause for the jaundice could be found, apart from the fatty acid oxidation disorder. Liver histology showed diffuse, predominately macrovesicular steatosis, hepatocellular and canalicular cholestasis but no bile duct paucity or evidence of large duct obstruction. The liver dysfunction resolved in 4-7 weeks.

| S-EPMC3575043 | biostudies-literature

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