scholarly journals Interplay between Thyroid Hormones and Stearoyl-CoA Desaturase 1 in the Regulation of Lipid Metabolism in the Heart

2020 ◽  
Vol 22 (1) ◽  
pp. 109
Author(s):  
Adam Olichwier ◽  
Volodymyr V. Balatskyi ◽  
Marcin Wolosiewicz ◽  
James M. Ntambi ◽  
Pawel Dobrzyn
Keyword(s):  
Fatty Acid ◽  
Lipid Metabolism ◽  
Thyroid Hormones ◽  
Fatty Acid Oxidation ◽  
Monounsaturated Fatty Acids ◽  
Thyroid Stimulating Hormone ◽  
Acid Oxidation ◽  
Expression Of Genes ◽  
Triglyceride Content ◽  
Stearoyl Coa Desaturase

Stearoyl-CoA desaturase 1 (SCD1), an enzyme that is involved in the biosynthesis of monounsaturated fatty acids, induces the reprogramming of cardiomyocyte metabolism. Thyroid hormones (THs) activate both lipolysis and lipogenesis. Many genes that are involved in lipid metabolism, including Scd1, are regulated by THs. The present study used SCD1 knockout (SCD1−/−) mice to test the hypothesis that THs are important factors that mediate the anti-steatotic effect of SCD1 downregulation in the heart. SCD1 deficiency decreased plasma levels of thyroid-stimulating hormone and thyroxine and the expression of genes that regulate intracellular TH levels (i.e., Slc16a2 and Dio1-3) in cardiomyocytes. Both hypothyroidism and SCD1 deficiency affected genomic and non-genomic TH pathways in the heart. SCD1 deficiency is known to protect mice from genetic- or diet-induced obesity and decrease lipid content in the heart. Interestingly, hypothyroidism increased body adiposity and triglyceride and diacylglycerol levels in the heart in SCD1−/− mice. The accumulation of triglycerides in cardiomyocytes in SCD1−/− hypothyroid mice was caused by the activation of lipogenesis, which likely exceeded the upregulation of lipolysis and fatty acid oxidation. Lipid accumulation was also observed in the heart in wildtype hypothyroid mice compared with wildtype control mice, but this process was related to a reduction of triglyceride lipolysis and fatty acid oxidation. We also found that simultaneous SCD1 and deiodinase inhibition increased triglyceride content in HL-1 cardiomyocytes, and this process was related to the downregulation of lipolysis. Altogether, the present results suggest that THs are an important part of the mechanism of SCD1 in cardiac lipid utilization and may be involved in the upregulation of energetic metabolism that is associated with SCD1 deficiency.

scholarly journals Leptin Regulates Peripheral Lipid Metabolism Primarily through Central Effects on Food Intake

Endocrinology ◽  
2008 ◽  
Vol 149 (11) ◽  
pp. 5432-5439 ◽  
Author(s):  
Xavier Prieur ◽  
Y. C. Loraine Tung ◽  
Julian L. Griffin ◽  
I. Sadaf Farooqi ◽  
Stephen O'Rahilly ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Lipid Metabolism ◽  
Food Intake ◽  
Fatty Acid Oxidation ◽  
Liver Weight ◽  
Metabolic Effects ◽  
Acid Oxidation ◽  
Mediated Effects ◽  
Expression Of Genes ◽  
Acyl Coenzyme A

The metabolic effects of leptin may involve both centrally and peripherally mediated actions with a component of the central actions potentially independent of alterations in food intake. Ob/ob mice have significant abnormalities in lipid metabolism, correctable by leptin administration. We used ob/ob mice to study the relative importance of the subtypes of actions of leptin (central vs. peripheral; food intake dependent vs. independent) on lipid metabolism. Mice were treated for 3 d with leptin, either centrally [intracerebroventricular (icv)] or peripherally (ip), and compared with mice pair-fed to the leptin-treated mice (PF) and with ad libitum-fed controls (C). All treatment groups (icv, ip, PF) showed indistinguishable changes in liver weight; hepatic steatosis; hepatic lipidemic profile; and circulating free fatty acids, triglycerides, and cholesterol lipoprotein profile. Changes in the expression of genes involved in lipogenesis and fatty acid oxidation in liver, muscle, and white fat were broadly similar in ip, icv, and PF groups. Leptin (both icv and ip) stimulated expression of both mitochondrial and peroxisomal acyl-coenzyme A oxidase (liver) and peroxisomal proliferator-activated receptor-α (skeletal muscle) to an extent not replicated by pair feeding. Leptin had profound effects on peripheral lipid metabolism, but the majority were explained by its effects on food intake. Leptin had additional centrally mediated effects to increase the expression of a limited number of genes concerned with fatty acid oxidation. Whereas we cannot exclude direct peripheral effects of leptin on certain aspects of lipid metabolism, we were unable to detect any such effects on the parameters measured in this study.

scholarly journals Maternal obesity alters placental lysophosphatidylcholines, lipid storage, and the expression of genes associated with lipid metabolism‡

2020 ◽  
Author(s):  
Katie L Bidne ◽  
Alana L Rister ◽  
Andrea R McCain ◽  
Brianna D Hitt ◽  
Eric D Dodds ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Fatty Acid ◽  
Lipid Metabolism ◽  
Maternal Obesity ◽  
Nutrient Transport ◽  
Digital Pcr ◽  
Lipid Profiles ◽  
Lipid Storage ◽  
Acid Oxidation ◽  
Expression Of Genes

Abstract Dyslipidemia is a characteristic of maternal obesity and previous studies have demonstrated abnormalities in fatty acid oxidation and storage in term placentas. However, there is little information about the effect of pre-pregnancy obesity on placental lipid metabolism during early pregnancy. The objective of this study was to determine the relationship between lipid profiles and markers of metabolism in placentas from obese and lean dams at midgestation. Mice were fed a western diet (WD) or normal diet (ND) and lysophosphatidylcholines (LPCs) and/or phosphatidylcholines (PCs) were measured in dam circulation and placenta sections using liquid chromatography–tandem mass spectrometry and mass spectrometry imaging, respectively. In WD dam, circulating LPCs containing 16:1, 18:1, 20:0, and 20:3 fatty acids were increased and 18:2 and 20:4 were decreased. In WD placenta from both sexes, LPC 18:1 and PC 36:1 and 38:3 were increased. Furthermore, there were moderate to strong correlations between LPC 18:1, PC 36:1, and PC 38:3. Treatment-, spatial-, and sex-dependent differences in LPC 20:1 and 20:3 were also detected. To identify genes that may regulate diet-dependent differences in placenta lipid profiles, the expression of genes associated with lipid metabolism and nutrient transport was measured in whole placenta and isolated labyrinth using droplet digital PCR and Nanostring nCounter assays. Several apolipoproteins were increased in WD placentas. However, no differences in nutrient transport or fatty acid metabolism were detected. Together, these data indicate that lipid storage is increased in midgestation WD placentas, which may lead to lipotoxicity, altered lipid metabolism and transport to the fetus later in gestation.

scholarly journals Leptin Augments the Acute Suppressive Effects of Insulin on Hepatic Very Low-Density Lipoprotein Production in Rats

Endocrinology ◽  
2009 ◽  
Vol 150 (5) ◽  
pp. 2169-2174 ◽  
Author(s):  
Wan Huang ◽  
Anantha Metlakunta ◽  
Nikolas Dedousis ◽  
Heidi K. Ortmeyer ◽  
Maja Stefanovic-Racic ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Lipid Metabolism ◽  
Fatty Acid Oxidation ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Saline Control ◽  
Acid Oxidation ◽  
Very Low Density Lipoprotein ◽  
Low Density ◽  
Vldl Metabolism

It is well established that leptin increases the sensitivity of carbohydrate metabolism to the effects of insulin. Leptin and insulin also have potent effects on lipid metabolism. However, the effects of leptin on the regulation of liver lipid metabolism by insulin have not been investigated. The current study addressed the effects of leptin on insulin-regulated hepatic very low-density lipoprotein (VLDL) metabolism in vivo in rats. A 90-min hyperinsulinemic/euglycemic clamp (4 mU/kg · min−1) reduced plasma VLDL triglyceride (TG) by about 50% (P < 0.001 vs. saline control). Importantly, a leptin infusion (0.2 μg/kg · min−1) in combination with insulin reduced plasma VLDL-TG by about 80% (P < 0.001 vs. insulin alone). These effects did not require altered skeletal muscle lipoprotein lipase activity but did include differential effects of insulin and leptin on liver apolipoprotein (apo) B and TG metabolism. Thus, insulin decreased liver and plasma apoB100/B48 levels (∼50%, P < 0.01), increased liver TGs (∼20%, P < 0.05), and had no effect on fatty acid oxidation. Conversely, leptin decreased liver TGs (∼50%, P < 0.01) and increased fatty acid oxidation (∼50%, P < 0.01) but had no effects on liver or plasma apoB levels. Importantly, the TG-depleting and prooxidative effects of leptin were maintained in the presence of insulin. We conclude that leptin additively increases the suppressive effects of insulin on hepatic and systemic VLDL metabolism by stimulating depletion of liver TGs and increasing oxidative metabolism. The net effect of the combined actions of insulin and leptin is to decrease the production and TG content of VLDL particles.

A Case of Mistaken Identity

2005 ◽  
Vol 288 (1) ◽  
pp. H448-H448 ◽  
Author(s):  
Andreas Stahl
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Early Development ◽  
Mammalian Species ◽  
Expression Patterns ◽  
Acid Oxidation ◽  
Published Data ◽  
Acid Uptake ◽  
Expression Of Genes ◽  
Cpt I

The heart is a unique organ that can use several fuels for energy production. During development, the heart undergoes changes in fuel supply, and it must be able to respond to these changes. We have examined changes in the expression of several genes that regulate fuel transport and metabolism in rat hearts during early development. At birth, there was increased expression of fatty acid transporters and enzymes of fatty acid metabolism that allow fatty acids to become the major source of energy for cardiac muscle during the first 2 wk of life. At the same time, expression of genes that control glucose transport and oxidation was downregulated. After 2 wk, expression of genes for glucose uptake and oxidation was increased, and expression of genes for fatty acid uptake and utilization was decreased. Expression of carnitine palmitoyltransferase I (CPT I) isoforms during development was different from published data obtained from rabbit hearts. CPT Iα and Iβ isoforms were both highly expressed in hearts before birth, and both increased further at birth. Only after the second week did CPT Iα expression decrease appreciably below the level of CPT Iβ expression. These results represent another example of different expression patterns of CPT I isoforms among various mammalian species. In rats, changes in gene expression followed nutrient availability during development and may render cardiac fatty acid oxidation less sensitive to factors that influence malonyl-CoA content (e.g., fluctuations in glucose concentration) and thereby favor fatty acid oxidation as an energy source for cardiomyocytes in early development.

scholarly journals Intracellular localization of AMP deaminase and its novel role in BCAA and lipid metabolism in diabetic cardiomyopathy

2021 ◽  
Vol 42 (Supplement_1) ◽  
Author(s):  
T Ogawa ◽  
H Kouzu ◽  
A Osanami ◽  
Y Tatekoshi ◽  
H Oshima ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Lipid Metabolism ◽  
Fatty Acid Oxidation ◽  
Lipid Droplets ◽  
Intracellular Localization ◽  
Fold Increase ◽  
Acid Oxidation ◽  
Transcriptional Level ◽  
Amp Deaminase ◽  
Funding Sources

Abstract Background A metabolomic study in the human heart suggested a pivotal role of amino acid (AA) metabolism in fatty acid oxidation, which is dysregulated in type 2 diabetes mellitus (T2DM) and heart failure. We previously reported that aberrant up-regulation of AMP deaminase 3 (AMPD3) impairs cardiac energetics in T2DM hearts, and AMPD3 was recently shown to be activated by fasting and to promote AA metabolism and fatty acid oxidation in skeletal muscle. A sodium glucose cotransporter 2 inhibitor (SGLT2i) has been shown to augment systemic AA metabolism, but its effect on cardiac AA metabolism remains unknown. Purpose We hypothesized that AMPD3 has a role in AA and lipid metabolism in cardiomyocytes and that the protective effect of an SGLT2i in diabetic hearts is mediated by modification of AA and lipid metabolism. Methods and results Proteomic analyses of AMPD3 immunoprecipitates in rat hearts revealed that AMPD3 interacted with the E1α and E2 components of the BCKDH complex, a rate-limiting enzyme of branched-chain AA (BCAA) catabolism. Immunoblotting using subcellular fractions revealed that BCKDH localized not only in the mitochondria matrix but also in the cytosol and endoplasmic reticulum (ER) and that AMPD3 interacted with BCKDH in the cytosol and ER. Despite comparable expression of BCKDH components and phosphorylation of E1α at Ser293, significant accumulation of BCAA was observed in T2DM rats (OLETF; 317±30 nmol/g) compared to that in control rats (LETO; 213±16 nmol/g), and the accumulation of BCAA was accompanied by up-regulation of AMPD3 in the cytosol and ER by 98% and 231%, respectively. In cardiomyocytes, disruption of BCAA catabolism by knockdown of BCKDH-E1α resulted in a 5.8-fold increase in AMPD3 at the transcriptional level and blunted lipid droplet biogenesis in response to a long-chain fatty acid challenge. Next, myocardial infarction (MI) was induced in LETO and OLETF pretreated with empagliflozin (10 mg/kg/day, 14 days) or a vehicle. Pathway analysis of cardiac metabolites revealed arginine biosynthesis and BCAA metabolism as the most significantly changed pathways with empagliflozin, with BCAA (791±187 nmol/g), glutamate, glutamine and urea being significantly increased. Empagliflozin restored myocardial ATP and survival after MI in OLETF to levels comparable to those in LETO. Electron microscopy showed a significantly higher prevalence of myocardium lipid droplets in OLETF, which was further increased by empagliflozin. Conclusions The results support the hypotheses that imbalance of extra-mitochondrial AMPD3-BCKDH interaction underlies dysregulated BCAA metabolism in T2DM hearts and that activation of cardiac AA metabolism by an SGLT2i normalizes fatty acid overload through sequestration into intracellular lipid droplets. FUNDunding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Boehringer Ingelheim

scholarly journals Perilipin 5 S155 phosphorylation by PKA is required for the control of hepatic lipid metabolism and glycemic control

2020 ◽  
pp. jlr.RA120001126
Author(s):  
Stacey N Keenan ◽  
William DeNardo ◽  
Jieqiong Lou ◽  
Ralf B. Schittenhelm ◽  
Magdalene K. Montgomery ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Lipid Metabolism ◽  
Glycemic Control ◽  
Fatty Acid Oxidation ◽  
Lipid Droplet ◽  
Critical Role ◽  
The Body ◽  
Acid Oxidation ◽  
Hepatic Lipid Metabolism ◽  
Hepatic Lipid

Perilipin (PLIN) 5 is a lipid droplet-associated protein that coordinates intracellular lipolysis in highly oxidative tissues and is thought to regulate lipid metabolism in response to phosphorylation by protein kinase A (PKA). We sought to identify PKA phosphorylation sites in PLIN5 and assess their functional relevance in cultured cells and the livers of mice. We detected phosphorylation on S155, S161 and S163 of recombinant PLIN5 by PKA in vitro and identified S155 as a functionally important site for lipid metabolism. Expression of phosphorylation-defective PLIN5 S155A in Plin5 null cells resulted in decreased rates of lipolysis and triglyceride-derived fatty acid oxidation compared with cells expressing wildtype PLIN5. These differences in lipid metabolism were not associated with differences in the cellular distribution of PLIN5. Rather, FLIM-FRET analysis of protein-protein interactions showed that PLIN5 S155 phosphorylation regulates PLIN5 interaction with adipose triglyceride lipase (ATGL) at the lipid droplet, but not with the co-activator of ATGL, α-β hydrolase domain-containing 5 (ABHD5). Re-expression of PLIN5 S155A in the liver of Plin5 liver-specific null mice reduced lipolysis when compared to mice with wildtype PLIN5 re-expression, but was not associated with other changes in hepatic lipid metabolism, such as fatty acid oxidation, de novo lipogenesis and triglyceride secretion. Furthermore, glycemic control was impaired in mice with expression of PLIN5 S155A compared with mice expressing PLIN5. Together, these studies demonstrate that PLIN5 S155 is required for PKA-mediated lipolysis and builds on the body of evidence demonstrating a critical role for PLIN5 in coordinating lipid and glucose metabolism

scholarly journals CDKN2A/p16INK4a suppresses hepatic fatty acid oxidation through the AMPKα2-SIRT1-PPARα signaling pathway

2020 ◽  
Vol 295 (50) ◽  
pp. 17310-17322
Author(s):  
Yann Deleye ◽  
Alexia Karen Cotte ◽  
Sarah Anissa Hannou ◽  
Nathalie Hennuyer ◽  
Lucie Bernard ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Lipid Metabolism ◽  
Fatty Acid Oxidation ◽  
Lipid Droplet ◽  
Acid Oxidation ◽  
Hepatic Lipid Metabolism ◽  
Hepatic Lipid ◽  
Hepatic Fatty Acid Oxidation

In addition to their well-known role in the control of cellular proliferation and cancer, cell cycle regulators are increasingly identified as important metabolic modulators. Several GWAS have identified SNPs near CDKN2A, the locus encoding for p16INK4a (p16), associated with elevated risk for cardiovascular diseases and type-2 diabetes development, two pathologies associated with impaired hepatic lipid metabolism. Although p16 was recently shown to control hepatic glucose homeostasis, it is unknown whether p16 also controls hepatic lipid metabolism. Using a combination of in vivo and in vitro approaches, we found that p16 modulates fasting-induced hepatic fatty acid oxidation (FAO) and lipid droplet accumulation. In primary hepatocytes, p16-deficiency was associated with elevated expression of genes involved in fatty acid catabolism. These transcriptional changes led to increased FAO and were associated with enhanced activation of PPARα through a mechanism requiring the catalytic AMPKα2 subunit and SIRT1, two known activators of PPARα. By contrast, p16 overexpression was associated with triglyceride accumulation and increased lipid droplet numbers in vitro, and decreased ketogenesis and hepatic mitochondrial activity in vivo. Finally, gene expression analysis of liver samples from obese patients revealed a negative correlation between CDKN2A expression and PPARA and its target genes. Our findings demonstrate that p16 represses hepatic lipid catabolism during fasting and may thus participate in the preservation of metabolic flexibility.

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