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PubMed1981

Fatty acid metabolism in phorbol ester-differentiating human leukemia cells.

Human promyelocytic leukemia cells (HL-60) undergo differentiation when treated with the tumor promoter, 12-O-tetradecanoylphorbol-13-acetate (TPA). As the primary target for TPA action is membranes, studies were undertaken to determine whether phorbol ester exposure would influence fatty acid metabolism in these cells. In cells incubated with labeled fatty acids for 1 hr, the percentage of distribution of lipid radioactivity is highest in the phospholipid fraction of control cultures, whereas in TPA-supplemented cells, substantially more label is associated with triacylglycerols. The specific activity of phospholipids and triacylglycerols was lower in treated than in control cells; however, the amount of cellular triacylglycerols increased 3.2-fold (lipid per mg protein). The increase in the amount of cellular phospholipids in TPA-treated cells is not as pronounced (approximately 50% above control), and this only occurs at higher concentrations of TPA. At early times after TPA exposure, there is no stimulation of the cellular uptake of labeled fatty acids; however, differentiating cells (24 to 48 hr of TPA), when incubated with label, contained more radioactivity than did control cultures. Cells treated with TPA for 48 hr show a marked decrease in the conversion of [1-14C]stearic acid to monoenoic product (22% of control); this decrease is dose dependent and occurs within 24 to 48 hr of treatment. Although the phospholipid fatty acid composition of differentiating cells was similar to control cells, acyl groups of triacylglycerols isolated from treated cells showed a marked decrease in the percentage of unsaturates. These data provide evidence which demonstrates that TPA treatment of HL-60 cells has a profound effect on fatty acid metabolism. The lack of an effect of TPA on fatty acid metabolism after short-term exposure to the promoter suggests that the modifications observed may be the result of cellular differentiation rather than a direct effect exerted by the presence of TPA in the culture media.

Carcinogens↗
PubMed1987

Effect of a high-fat diet with partially hydrogenated fish oil on long-chain fatty acid metabolizing enzymes in subcellular fractions of rat liver.

Hepatic metabolism of long-chain fatty acids were studied in young male rats fed a semisynthetic diet containing 20% (w/w) partially hydrogenated fish oil (PHFO)2, with or without 2% (w/w) linoleic acid. The enzymic activities involved in the formation and breakdown of long-chain acyl-CoA were both increased in the animals fed the semisynthetic diet, compared to pellet-fed control animals. Thus, the specific palmitoyl-CoA synthetase activity increased slightly in both the mitochondrial (1.4-fold) and the microsomal (1.6-fold) fractions. In the peroxisome-enriched fraction the activity was increased (about 2.6-fold) only on addition of linoleic acid to the diet. The data are consistent with an increased catabolism of long-chain fatty acids by a peroxisomal and a mitochondrial pathway. Thus, the total carnitine palmitoyltransferase activity increased 2-fold in the mitochondrial fraction, and was partly prevented by added linoleic acid. Peroxisomal beta-oxidation activity was also increased (about 7-fold) in livers of PHFO-fed rats, but did not change when linoleic acid was added. The PHFO-fed rats also revealed elevated capacity for hydrolysis of palmitoyl-CoA in both the mitochondrial (2.4-fold) and the cytosolic (2.0-fold) fractions and the latter was almost completely and selectively prevented by added linoleic acid. The s values of mitochondria and peroxisomes varied with the dietary regime, and some of the observed changes in the specific activities of the fatty acid metabolizing enzymes with multiple subcellular localization can be explained as an effect of changes in the s values of the organelles. Thus, the s value of mitochondria increased 1.8-fold as a result of PHFO feeding, but was fully prevented by linoleic acid in the diet. On the other hand, the s values of peroxisomes decreased by about 50% on feeding a PHFO diet, and by about 25% with added linoleic acid.

Animals↗
PubMed1997

Detection of impaired fatty acid metabolism in right ventricular hypertrophy: assessment by I-123 beta-methyl iodophenyl pentadecanoic acid (BMIPP) myocardial single-photon emission computed tomography.

Fatty acid metabolism has been reported to be impaired earlier than myocardial blood flow in left ventricular hypertrophic myocardium, e.g., in hypertrophic cardiomyopathy or hypertensive heart disease. The purpose of this study was to determine whether impaired fatty acid metabolism also occurs in right ventricular (RV) hypertrophy. The subjects consisted of 6 patients with chronic obstructive pulmonary disease, 4 with primary pulmonary hypertension, 2 each with refractory pulmonary tuberculosis, tricuspid insufficiency, pulmonary embolism, 1 each with atrial septal defect, ventricular septal defect (Eisenmenger complex), Ebstein anomaly, and endocardial defect, and 7 healthy controls. SPECT imaging with Tl-201 (Tl) and I-123 beta-methyliodophenyl pentadecanoic acid (BMIPP), and Tc-99m RBC first pass and gated blood pool scintigraphy were performed. Based on Tl planar images, the subjects were classified into 3 groups: 7 patients with no RV visualization (Group A), 11 with moderate RV visualization (Group B) and 9 with marked RV visualization (Group C). As a semi-quantitative evaluation by Tl myocardial SPECT, 3 regions in 3 representative short axial images were divided into 9 segments, each of which was graded from 0 to +3, and their sum was calculated as the RV score. The right ventricular ejection fraction (RVEF) and the left ventricular ejection fraction were obtained by Tc-99m RBC cardiac scintigraphy. The groups with marked visualization of the right ventricle had lower RVEF (p < 0.01), and there was a good correlation between the RVEF and the RV score with both Tl and BMIPP (Tl: r = -0.79, BMIPP: r = -0.70). Although a good correlation was demonstrated between the RV score with Tl and BMIPP in Groups A and B (r = 0.86, p < 0.001), in Group C, in which there was marked RV T1 visualization, the RV score with BMIPP was significantly smaller than with Tl (BMIPP vs. Tl: 11.5 +/- 3.7 vs. 16.4 +/- 3.8, p < 0.01). These findings suggest that impaired fatty acid metabolism may exist in severely hypertrophic right ventricle due to RV overload.

Aged↗
PubMed2005

Does endogenous fatty acid metabolism allow cancer cells to sense hypoxia and mediate hypoxic vasodilatation? Characterization of a novel molecular connection between fatty acid synthase (FAS) and hypoxia-inducible factor-1alpha (HIF-1alpha)-related expression of vascular endothelial growth factor (VEGF) in cancer cells overexpressing her-2/neu oncogene.

Her-2/neu (erbB-2) oncogene overexpression is associated with increased tumor progression and metastasis. Fatty acid synthase (FAS), the key lipogenic enzyme responsible for the endogenous synthesis of fatty acids, has been shown to be one of the genes regulated by Her-2/neu at the level of transcription, translation, and biosynthetic activity. Interestingly, we recently established that both pharmacological inhibition of FAS activity and silencing of FAS gene expression specifically suppress Her-2/neu oncoprotein expression and tyrosine-kinase activity in breast and ovarian Her-2/neu overexpressors. Unraveling the functional organization of this novel bi-directional molecular connection between Her-2/neu and FAS-dependent neoplastic lipogenesis is a major challenge that the field is only beginning to take on. Considering that Her-2/neu overexpression correlates with increased expression of the hypoxia inducible factor-1alpha (HIF-1alpha), which, in a mitogen-activated protein kinase (MAPK)-dependent manner, plays a key role in the expression of several genes including cytokines such as vascular endothelial growth factor (VEGF), we hypothesized that FAS blockade should result in a concomitant down-regulation of VEGF. Unexpectedly, the specific inhibition of the de novo fatty acid synthesis with the small-molecule inhibitor of FAS activity C75 resulted in a dramatic dose-dependent enhancement (up to 500% increase) of VEGF secretion in Her-2/neu-overexpressing SK-Br3, BT-474, and SKOV3 cancer cells. Concurrently, FAS blockade drastically activated MAPK and promoted further a prominent accumulation of HIF-1alpha in Her-2/neu overexpressors. Moreover, U0126-induced inhibition of MAPK activity completely abolished C75-induced up-regulation of HIF-1alpha expression and VEGF secretion, whereas it did not modulate C75-induced down-regulation of Her-2/neu oncogene. Importantly, RNA interference (RNAi)-mediated silencing of the FAS gene recapitulated C75's effects by up-regulating VEGF secretion, MAPK activation and HIF-1alpha expression. Therefore, it appears that perturbation of cancer-associated endogenous fatty metabolism triggers a "hypoxia-like" (oxygen-independent) condition that actively rescues Her-2/neu-dependent MAPK --> HIP-1alpha --> VEGF cascade. It is tempting to suggest that an intact FAS-catalyzed endogenous fatty acid metabolism is a necessary metabolic adaptation to support the enhanced ability of Her-2/neu-overexpressing cancer cells to survive cellular hypoxia in a HIF-alpha-dependent manner.

Cell Hypoxia↗
PubMed1996

Abnormalities in hepatic fatty-acid metabolism in a surfactant/influenza B virus mouse model for acute encephalopathy.

Abnormalities in fatty-acid metabolism are believed to play a role in nonspecific acute encephalopathy (AE) with hepatomegaly, although the specific nature of these abnormalities and their temporal relationship to the pathology are not well defined. We have examined hepatic fatty-acid beta-oxidation and metabolism in a mouse model for AE in which neonatal mice were exposed dermally to nontoxic doses of the industrial surfactant, Toximul MP8 (Tox), daily from days 1 to 12 after birth, and then infected with a sublethal dose (LD30) of mouse-adapted human influenza B (Lee) virus (FluB). The number of deaths in the group treated with Tox + FluB were significantly higher than those in the group infected with virus alone. Under optimal in vitro assay conditions, beta-oxidation of [1-14C]palmitic acid was approximately 15% higher in liver homogenates from mice painted with Tox for 12 days (P < 0.02); catabolism of [1-14C]octanoic acid to 14C-labelled water-soluble products (14C-WSP) and 14CO2 was unaltered by Tox. Infecting Tox-free mice with FluB inhibited beta-oxidation of both [1-14C]palmitate and [1-14C]octanoate by 20-30% (P < 0.001). On days 18-19, when most Tox + FluB-dependent deaths occurred, the inhibition of oxidation was increased to approximately 50% in mice given the combined treatment. Treatment of the mice with Tox/FluB also altered the pattern of incorporation of fatty acids into complex lipids. Hepatic levels of thiobarbituric acid reactive substance (TBARS), a marker for lipid peroxides, were approximately 15% higher in Tox-painted than in control mice (P < 0.01); FluB alone had no effect. In Tox + FluB-treated animals, TBARS levels were > 2-fold higher than in any other experimental group (P < 0.001). These studies demonstrated that nasally-administered FluB has profound effects on hepatic fatty-acid metabolism, particularly beta-oxidation. Exacerbation of this and related effects by exposing young animals to xenobiotic surfactants could be the basis of surfactant-mediated potentiation of virus-induced mortality.

Adenosine Triphosphate↗
PubMed1997

[Assessment of 123I-beta-methyl iodophenyl pentadecanoic acid (BMIPP) myocardial scintigraphy in patients of chronic right ventricular overload--fatty acid metabolism in right ventricular myocardium].

An investigation on the right ventricular pressure level and the abnormalities in the fatty acid metabolism of myocardium was made using 123I-beta-methyl-iodophenyl pentadecanoic acid (BMIPP) myocardial SPECT in patients with chronic right ventricular overloading. Twenty patients who presented with right ventricular systolic pressure (RVSP) of 35 mmHg or more were used as the subjects. Dual myocardial SPECT with 201TlCl (Tl) and BMIPP was carried out for the subjects and RVc/LVc, a ratio of radioactivity count incorporated in the right ventricular free wall to the left one was determined for Tl and BMIPP. And the correlations between RVc/LVc and RVSP, and RVc/LVc and RVSP/LVSP were examined. The subjects were classified into 3 groups based on the RVSP levels and the count ratio, BMIPP/Tl was compared among the three groups. With respect of Tl uptake, there were significant, positive correlations between RVc/LVc and RVSP (correlation coefficient r = 0.51, p < 0.05) and between RVc/LVc and RVSP/LVSP (correlation coefficient r = 0.59, p < 0.01). On the other hand, no significant correlation was found between them with respect of the uptake of BMIPP. The BMIPP/Tl ratio in the group with higher than 80 mmHg of RVSP was 0.82 +/- 0.06, which was significantly lower than the ratio's for two groups of less than 80 mmHg; 0.91 +/- 0.07 and 0.98 +/- 0.04 in the group with 35-49 and 50-79 mmHg of RVSP, respectively. These results show that when compared with BMIPP, Tl is superior for the estimation of right ventricular pressure. For the patients with right ventricular overloading, it was suggested that when RVSP reaches 80 mmHg or more, there appear some disorders in the fatty acid metabolism in the right ventricular myocardium.

Aged↗
PubMed1993

Fatty-acid metabolism and the pathogenesis of hepatocellular carcinoma: review and hypothesis.

Despite increasing understanding of the genetic control of cell growth and the identification of several involved chemical and infectious factors, the pathogenesis of clinical and experimental hepatocellular carcinoma remains unknown. Available evidence is consistent with the possibility that selected changes in the hepatocellular metabolism of long-chain fatty acids may contribute significantly to this, process. Specifically, studies of the peroxisome proliferators, a diverse group of xenobiotics that includes the fibrate class of hypolipidemic drugs, suggest that increased fatty acid oxidation by way of extramitochondrial pathways (i.e., omega-oxidation in the smooth endoplasmic reticulum and beta-oxidation in the peroxisomes) results in a corresponding increase in the generation of hydrogen peroxide and, thus, oxidative stress. This in turn leads to alterations in gene expression and in DNA itself. We also review evidence supporting a potentially decisive influence of particular aspects of hepatocellular fatty acid metabolism in determining the activity of the extramitochondrial pathways. Moreover, certain intermediates of extramitochondrial fatty acid oxidation (e.g., the long-chain dicarboxylic fatty acids) impair mitochondrial function and are implicated as modulators of gene expression through their interaction with the peroxisome proliferator-activated receptor. Finally, the occurrence of hepatic tumors in type I glycogen storage disease (glucose-6-phosphatase deficiency) may exemplify this general mechanism, which may also contribute to nonneoplastic liver injury and to tumorigenesis in other tissues.

Animals↗
PubMed2000

Improvement in cardiac function and free fatty acid metabolism in a case of dilated cardiomyopathy with CD36 deficiency.

A 27-year-old man diagnosed as having dilated cardiomyopathy (DCM) without myocardial accumulation of 123I-beta-methyl-iodophenylpentadecanoic acid, and he was found to have type I CD36 deficiency. This abnormality of cardiac free fatty acid metabolism was also confirmed by other methods: 18F-fluoro-2-deoxyglucose positron emission tomography, measurements of myocardial respiratory quotient and cardiac fatty acid uptake. Although the type I CD36 deficiency was reconfirmed after 3 months, the abnormal free fatty acid metabolism improved after carvedilol therapy and was accompanied by improved cardiac function. Apart from a cause-and-effect relationship, carvedilol can improve cardiac function and increase free fatty acid metabolism in patients with both DCM and CD36 deficiency.

Adrenergic beta-Antagonists↗
PubMed1992

Changes of hepatic fatty acid metabolism produced by chronic thioacetamide administration in rats.

Hepatic mitochondrial functions related to fatty acid metabolism, including the respiratory control ratio, fatty acid oxidative capacity and carnitine palmitoyltransferase I activity, were studied in vitro with mitochondria isolated from rats treated with thioacetamide for up to 12 wk. The levels of ketone bodies, carnitine, carnitine esters and malonyl-coenzyme A were also determined in liver extracts. Polarography of mitochondrial respiration from succinate or glutamate plus malate showed a lower respiratory control ratio in thioacetamide-treated rats, whereas uncoupled oxygen consumption was not altered. This suggests that the mitochondrial respiratory chain capacity remained intact in the thioacetamide-treated rats. The oxygen consumption associated with palmitoyl-coenzyme A and palmitoyl-L-carnitine oxidation by isolated liver mitochondria was increased by thioacetamide treatment on both a per-mitochondrial protein and a per-total liver basis. The carnitine palmitoyl-transferase I activity; the tissue levels of ketone bodies, carnitine and carnitine esters; and the beta-hydroxybutyrate/acetoacetate ratio were all higher in the livers of thioacetamide-treated animals than in control livers, whereas the hepatic malonyl-coenzyme A level was decreased by thioacetamide. These results indicate the increased diversion of cytosolic long-chain acyl-coenzyme As into the mitochondria for beta-oxidation rather than their esterification and use in lipogenesis. These intrahepatic metabolic changes induced by chronic thioacetamide administration may reflect the whole-body catabolic state and can be seen as adaptive for maintaining energy homeostasis under conditions of impaired glucose tolerance.

Animals↗
PubMed1999

[Relationship between ventricular arrhythmias and myocardial fatty acid metabolism in patients with coronary heart disease: evaluation using iodine-123 beta-methyl-p-iodophenyl-pentadecanoic acid].

The effect of metabolic abnormalities of myocardial fatty acids on ventricular arrhythmias was evaluated by myocardial imaging with iodine-123 beta-methyl-p-iodophenyl-pentadecanoic acid (BMIPP) in 27 patients with coronary heart disease. The disturbance of myocardial blood flow was also evaluated using thallium-201 (Tl). The patients were divided into 2 groups based on the character of the premature ventricular contractions: Group A: number of contractions > or = 120 per day and/or consecutive contractions (n = 9, mean age 63.7 yr), and Group B, number of contractions < 120 per day and no consecutive contractions (n = 18, mean age 64.2 yr). Left ventricular ejection fraction was measured by left ventriculography, and significant coronary artery stenosis was defined as stenosis of 75% or greater. Cardiac scintigraphy was performed using single photon emission computed tomography with BMIPP at rest in 27 patients and in the early phase (early Tl) and delayed phase of Tl (delayed Tl) in 20 patients. BMIPP and Tl uptakes were scored as 0: absent, 1: moderately reduced, 2: mildly reduced and 3: normal in 7 segments of the left ventricular wall and then the total scores were calculated in each patient. Ejection fraction significantly correlated with the scores of BMIPP, and early and delayed Tl(p < 0.001, respectively), although the ejection fraction in Group A was significantly less than in Group B (51.2 +/- 16.7% vs 68.2 +/- 14.4%, p < 0.02). The BMIPP scores in Group A were significantly less than those in Group B (14.2 +/- 4.3 vs 17.2 +/- 3.1, p < 0.05), but the early and delayed Tl scores in Group A were not significantly different compared with those in Group B. The BMIPP scores showed no significant differences between the patients with and without significant coronary artery stenosis, but the early and delayed Tl scores in the patients with stenosis were significantly less than those in patients without stenosis (early Tl: 19.8 +/- 2.6 vs 16.8 +/- 2.8, p < 0.01; delayed Tl: 19.6 +/- 2.5 vs 16.8 +/- 3.1, p < 0.05). More patients had values of Tl minus BMIPP scores of at least 3 in Group A than in Group B (early Tl-BMIPP > or = 3: 66.7% vs 7.7%, p < 0.01; delayed Tl-BMIPP > or = 3: 50.0% vs 7.7%, p < 0.05). In patients with coronary heart disease, decreased ejection fraction is thought to be a major cause of ventricular arrhythmias, and also associated with abnormal myocardial metabolism and abnormal myocardial blood flow. Furthermore, ventricular arrhythmias were more closely correlated with abnormal metabolism of fatty acids than with disturbance of blood flow in the myocardium, and large mismatching between the 2 images may be related to risky ventricular arrhythmias in coronary heart disease.

Aged↗
PubMedDate not supplied

Effect of ethanol on fatty acid metabolism in cultured hepatocytes: dependency on incubation time and fatty acid concentration.

In a previous report it was shown that ethanol increases the rate of accumulation of triacylglycerol by 90% in hepatocytes in primary culture. This represents the first known suitable model for in vitro studies of the ethanol-induced fatty liver. The biochemical alterations causing this accumulation of triacylglycerol remain to be elucidated, however. In the present report it is shown that (1) the effect of ethanol exhibits a time lag of 6-9 hours (2) the increment in the content of triacylglycerol caused by ethanol is increased by increased concentrations of fatty acids (3) the fatty acid uptake is not affected by ethanol (4) fatty acid synthesis is inhibited 20% by ethanol (5) the contents of diacylglycerol and phospholipids are not affected by ethanol (6) addition of ethanol increases the cytosolic and mitochondrial redox levels. It is concluded that ethanol is likely to exert its effect on the accumulation of triacylglycerol by redistributing fatty acids between oxidation and triacylglycerol synthesis and/or between storage and secretion of triacylglycerol.

Animals↗
PubMed1996

Fatty acid metabolism in freshwater fish with particular reference to polyunsaturated fatty acids.

Fatty acids in fish can arise from two sources: synthesis de novo from non-lipid carbon sources within the animal, or directly from dietary lipid. Acetyl-CoA derived mainly from protein can be converted to saturated fatty acids via the combined action of acetyl-CoA carboxylase and fatty acid synthetase. The actual rate of fatty acid synthesis de novo is inversely related to the level of lipid in the diet. Freshwater fish can desaturate endogenously-synthesized fatty acids to monounsaturated fatty acids via a delta 9 desaturase but lack the necessary enzymes for complete de novo synthesis of polyunsaturated fatty acids which must therefore be obtained preformed from the diet. Most freshwater fish species can desaturate and elongate 18:2(n-6) and 18:3(n-3) to their C20 and C22 homologues but the pathways involved remain ill-defined. Cyclooxygenase and lipoxygenase enzymes can convert C20 polyunsaturated fatty acids to a variety of eicosanoid products. The dietary ratio of (n-3) to (n-6) polyunsaturated fatty acids influences the pattern of eicosanoids formed. The beta-oxidation of fatty acids can occur in both mitochondria and peroxisomes but mitochondrial beta-oxidation is quantitatively more important and can utilise a wide range of fatty acid substrates.

Animals↗
PubMed1989

Fatty acid metabolism in the heart during Escherichia coli sepsis in the rat.

Fatty acid metabolism was studied in fasted control, fasted Escherichia coli-treated, fed control, and fed E. coli-treated rats to find out whether the reduction in myocardial carnitine was associated with changes in oxidation and esterification of long chain fatty acids. Rats were made septic by injecting i.v. 8 X 10(7) live colonies of E. coli per 100 g body weight. Fed rats were infused intragastrically with a nutritionally adequate diet containing glucose plus fat for five days before inducing sepsis. Food was removed from the fasted rats after E. coli injection. Twenty-four hours later, the production of CO2 from [1-14C]palmitate was not altered in heart homogenates from fasted or fed E. coli-treated rats. In comparison to control rats, heart homogenates from fasted E. coli-treated rats incorporated 32% more [1-14C]palmitate into triglycerides. The heart content of triglycerides was also increased threefold during sepsis. Rates of esterification and lipid composition were not altered in the hearts from fed E. coli-treated rats. The increased rate of triglyceride synthesis in the hearts from fasted E. coli-treated rats appears to be due to a 40% higher content of glycerol 3-phosphate and 55% more activity of glycerol 3-phosphate acyltransferase. These results also suggest that the reduced content of myocardial carnitine that occurs during E. coli sepsis does not limit the availability of fatty acids for oxidation.

Animals↗
PubMed1992

HMG-CoA reductase inhibitors perturb fatty acid metabolism and induce peroxisomes in keratinocytes.

Topical lovastatin stimulates epidermal fatty acid synthesis in vivo; therefore, studies were undertaken to examine the effects of HMG-CoA reductase inhibitors on fatty acid metabolism in cultured keratinocytes. When exposed to fluindostatin or lovastatin for greater than or equal to 24 h, keratinocytes in serum-free media accumulated nile red-fluorescent lipid droplets. By 72 h, the triacylglycerol and phospholipid content were increased 2.5- and 1.3-fold, respectively. Reductase inhibitors (1-10 microM) increased fatty acid synthesis approximately 1.5-fold; increased synthesis was noted only after greater than 15 h exposure and was distributed among phospholipids and triacylglycerols. Oxidation of [14C]palmitate to CO2 was decreased greater than 50% in inhibitor-treated cultures, and label accumulated in triacylglycerols. Inhibitor-treated keratinocytes exhibited increased numbers of peroxisomes, using diaminobenzidene ultracytochemistry. Peroxisomal hyperplasia was also demonstrated by increased catalase activity (1.5- to 2.5-fold), increased dihydroxyacetone phosphate acyltransferase activity (1.4-fold) and increased peroxisomal (KCN-insensitive) fatty acid oxidation (1.4-fold) in inhibitor-treated cultures. Thus HMG-CoA reductase inhibitors increase fatty acid synthesis, induce triacylglycol and phospholipid accumulation, and induce peroxisomes in cultured keratinocytes. Coincubations with either low density lipoproteins or 25-hydroxycholesterol prevented both the peroxisomal hyperplasia and increased fatty acid synthesis, suggesting that these effects of reductase inhibitors may be linked to their effects on the cholesterol biosynthetic pathway.

Cells, Cultured↗
PubMed2003

Involvement of nitric oxide/cyclic GMP signaling pathway in the regulation of fatty acid metabolism in rat hepatocytes.

The role of nitric oxide (NO)/guanosine 3',5'-cyclic monophosphate (cGMP) signaling pathway in the regulation of fatty acid metabolism was investigated in rat hepatocytes. Treatment with NO donors, which are known to activate soluble guanylyl cyclase, inhibited in parallel fatty acid synthesis de novo and acetyl-CoA carboxylase activity. This effect was mimicked by 8-Br-cGMP and abolished by KT5823, a selective inhibitor of cGMP-dependent protein kinase (PKG). Furthermore, specific and hydrolysis-resistant activators of PKG, and inhibitors of Ca2+ release from endoplasmic reticulum, were also effective in inhibiting both fatty acid-synthesizing activities. These results suggest that this biological action of NO is regulated by a signaling cascade involving soluble guanylyl cyclase, cGMP, and PKG, and may be mediated, at least in part, by inhibition of Ca2+ release from endoplasmic reticulum. In addition, 8-Br-cGMP was able to stimulate fatty acid oxidation by two different mechanisms: the relieving of malonyl-CoA-dependent inhibition by lowering levels of this product of acetyl-CoA carboxylase, and a malonyl-CoA-independent stimulation of carnitine palmitoyltransferase I. Taken together, results of this study suggest that NO/cGMP signaling pathway is endowed with regulatory properties in fatty acid metabolism, and may have a physiological role in the control of this metabolism in liver.

Animals↗