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1.
J Lipid Res ; 65(6): 100558, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38729350

RESUMO

Metabolic dysfunction-associated steatotic liver disease is the most common form of liver disease and poses significant health risks to patients who progress to metabolic dysfunction-associated steatohepatitis. Fatty acid overload alters endoplasmic reticulum (ER) calcium stores and induces mitochondrial oxidative stress in hepatocytes, leading to hepatocellular inflammation and apoptosis. Obese mice have impaired liver sarco/ER Ca2+-ATPase (SERCA) function, which normally maintains intracellular calcium homeostasis by transporting Ca2+ ions from the cytoplasm to the ER. We hypothesized that restoration of SERCA activity would improve diet-induced steatohepatitis in mice by limiting ER stress and mitochondrial dysfunction. WT and melanocortin-4 receptor KO (Mc4r-/-) mice were placed on either chow or Western diet (WD) for 8 weeks. Half of the WD-fed mice were administered CDN1163 to activate SERCA, which reduced liver fibrosis and inflammation. SERCA activation also restored glucose tolerance and insulin sensitivity, improved histological markers of metabolic dysfunction-associated steatohepatitis, increased expression of antioxidant enzymes, and decreased expression of oxidative stress and ER stress genes. CDN1163 decreased hepatic citric acid cycle flux and liver pyruvate cycling, enhanced expression of mitochondrial respiratory genes, and shifted hepatocellular [NADH]/[NAD+] and [NADPH]/[NADP+] ratios to a less oxidized state, which was associated with elevated PUFA content of liver lipids. In sum, the data demonstrate that pharmacological SERCA activation limits metabolic dysfunction-associated steatotic liver disease progression and prevents metabolic dysfunction induced by WD feeding in mice.


Assuntos
Fígado , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático , Animais , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Camundongos , Fígado/metabolismo , Fígado/patologia , Masculino , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Estresse do Retículo Endoplasmático , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Dieta Ocidental/efeitos adversos , Camundongos Knockout
2.
Cells ; 11(19)2022 09 27.
Artigo em Inglês | MEDLINE | ID: mdl-36230994

RESUMO

Disturbances in cardiac lipid metabolism are associated with the development of cardiac hypertrophy and heart failure. Spontaneously hypertensive rats (SHRs), a genetic model of primary hypertension and pathological left ventricular (LV) hypertrophy, have high levels of diacylglycerols in cardiomyocytes early in development. However, the exact effect of lipids and pathways that are involved in their metabolism on the development of cardiac dysfunction in SHRs is unknown. Therefore, we used SHRs and Wistar Kyoto (WKY) rats at 6 and 18 weeks of age to analyze the impact of perturbations of processes that are involved in lipid synthesis and degradation in the development of LV hypertrophy in SHRs with age. Triglyceride levels were higher, whereas free fatty acid (FA) content was lower in the LV in SHRs compared with WKY rats. The expression of de novo FA synthesis proteins was lower in cardiomyocytes in SHRs compared with corresponding WKY controls. The higher expression of genes that are involved in TG synthesis in 6-week-old SHRs may explain the higher TG content in these rats. Adenosine monophosphate-activated protein kinase phosphorylation and peroxisome proliferator-activated receptor α protein content were lower in cardiomyocytes in 18-week-old SHRs, suggesting a lower rate of ß-oxidation. The decreased protein content of α/ß-hydrolase domain-containing 5, adipose triglyceride lipase (ATGL) activator, and increased content of G0/G1 switch protein 2, ATGL inhibitor, indicating a lower rate of lipolysis in the heart in SHRs. In conclusion, the present study showed that the development of LV hypertrophy and myocardial dysfunction in SHRs is associated with triglyceride accumulation, attributable to a lower rate of lipolysis and ß-oxidation in cardiomyocytes.


Assuntos
Hipertrofia Ventricular Esquerda , Metabolismo dos Lipídeos , Monofosfato de Adenosina/farmacologia , Animais , Diglicerídeos/metabolismo , Ácidos Graxos não Esterificados/metabolismo , Hipertrofia Ventricular Esquerda/metabolismo , Hipertrofia Ventricular Esquerda/patologia , Lipase/metabolismo , Miócitos Cardíacos/metabolismo , PPAR alfa/metabolismo , Proteínas Quinases/metabolismo , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Triglicerídeos/metabolismo
3.
JCI Insight ; 6(12)2021 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-34156032

RESUMO

The liver is the major source of glucose production during fasting under normal physiological conditions. However, the kidney may also contribute to maintaining glucose homeostasis in certain circumstances. To test the ability of the kidney to compensate for impaired hepatic glucose production in vivo, we developed a stable isotope approach to simultaneously quantify gluconeogenic and oxidative metabolic fluxes in the liver and kidney. Hepatic gluconeogenesis from phosphoenolpyruvate was disrupted via liver-specific knockout of cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C; KO). 2H/13C isotopes were infused in fasted KO and WT littermate mice, and fluxes were estimated from isotopic measurements of tissue and plasma metabolites using a multicompartment metabolic model. Hepatic gluconeogenesis and glucose production were reduced in KO mice, yet whole-body glucose production and arterial glucose were unaffected. Glucose homeostasis was maintained by a compensatory rise in renal glucose production and gluconeogenesis. Renal oxidative metabolic fluxes of KO mice increased to sustain the energetic and metabolic demands of elevated gluconeogenesis. These results show the reciprocity of the liver and kidney in maintaining glucose homeostasis by coordinated regulation of gluconeogenic flux through PEPCK-C. Combining stable isotopes with mathematical modeling provides a versatile platform to assess multitissue metabolism in various genetic, pathophysiological, physiological, and pharmacological settings.


Assuntos
Gluconeogênese/genética , Rim/metabolismo , Fosfoenolpiruvato Carboxiquinase (GTP)/metabolismo , Animais , Isótopos de Carbono , Deutério , Rim/fisiologia , Masculino , Análise do Fluxo Metabólico , Camundongos , Camundongos Knockout , Fosfoenolpiruvato Carboxiquinase (GTP)/genética , Regulação para Cima
4.
Curr Opin Biotechnol ; 71: 1-8, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34048994

RESUMO

Identifying the factors and mechanisms that regulate metabolism under normal and diseased states requires methods to quantify metabolic fluxes of live tissues within their physiological milieu. A number of recent developments have expanded the reach and depth of isotope-based in vivo flux analysis, which have in turn challenged existing dogmas in metabolism research. First, minimally invasive techniques of intravenous isotope infusion and sampling have advanced in vivo metabolic tracer studies in animal models and human subjects. Second, recent breakthroughs in analytical instrumentation have expanded the scope of isotope labeling measurements and reduced sample volume requirements. Third, innovative modeling approaches and publicly available software tools have facilitated rigorous analysis of sophisticated experimental designs involving multiple tracers and expansive metabolomics datasets. These developments have enabled comprehensive in vivo quantification of metabolic fluxes in specific tissues and have set the stage for integrated multi-tissue flux assays.


Assuntos
Metabolômica , Software , Animais , Isótopos de Carbono , Humanos , Marcação por Isótopo , Análise do Fluxo Metabólico , Modelos Biológicos
5.
J Lipid Res ; 61(5): 707-721, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32086244

RESUMO

Fatty liver involves ectopic lipid accumulation and dysregulated hepatic oxidative metabolism, which can progress to a state of elevated inflammation and fibrosis referred to as nonalcoholic steatohepatitis (NASH). The factors that control progression from simple steatosis to NASH are not fully known. Here, we tested the hypothesis that dietary vitamin E (VitE) supplementation would prevent NASH progression and associated metabolic alterations induced by a Western diet (WD). Hyperphagic melanocortin-4 receptor-deficient (MC4R-/-) mice were fed chow, chow+VitE, WD, or WD+VitE starting at 8 or 20 weeks of age. All groups exhibited extensive hepatic steatosis by the end of the study (28 weeks of age). WD feeding exacerbated liver disease severity without inducing proportional changes in liver triglycerides. Eight weeks of WD accelerated liver pyruvate cycling, and 20 weeks of WD extensively upregulated liver glucose and oxidative metabolism assessed by 2H/13C flux analysis. VitE supplementation failed to reduce the histological features of NASH. Rather, WD+VitE increased the abundance and saturation of liver ceramides and accelerated metabolic flux dysregulation compared with 8 weeks of WD alone. In summary, VitE did not limit NASH pathogenesis in genetically obese mice, but instead increased some indicators of metabolic dysfunction.


Assuntos
Dieta Ocidental/efeitos adversos , Análise do Fluxo Metabólico , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Vitamina E/farmacologia , Animais , Antioxidantes/química , Antioxidantes/farmacologia , Interações Medicamentosas , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Hepatopatia Gordurosa não Alcoólica/metabolismo , Solubilidade
6.
Biochim Biophys Acta ; 1861(12 Pt A): 2029-2037, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27751891

RESUMO

Stearoyl-CoA desaturase 1 (SCD1) has recently been shown to be a critical control point in the regulation of cardiac metabolism and function. Peroxisome proliferator-activated receptor α (PPARα) is an important regulator of myocardial fatty acid uptake and utilization. The present study used SCD1 and PPARα double knockout (SCD1-/-/PPARα-/-) mice to test the hypothesis that PPARα is involved in metabolic changes in the heart that are caused by SCD1 downregulation/inhibition. SCD1 deficiency decreased the intracellular content of free fatty acids, triglycerides, and ceramide in the heart of SCD1-/- and SCD1-/-/PPARα-/- mice. SCD1 ablation in PPARα-/- mice decreased diacylglycerol content in cardiomyocytes. These results indicate that the reduction of fat accumulation in the heart associated with SCD1 deficiency occurs independently of the PPARα pathway. To elucidate the mechanism of the observed changes, we treated HL-1 cardiomyocytes with the SCD1 inhibitor A939572 and/or PPARα inhibitor GW6471. SCD1 inhibition decreased the level of lipogenic proteins and increased lipolysis, reflected by a decrease in the content of adipose triglyceride lipase inhibitor G0S2 and a decrease in the ratio of phosphorylated hormone-sensitive lipase (HSL) at Ser565 to HSL (pHSL[Ser565]/HSL). PPARα inhibition alone did not affect the aforementioned protein levels. Finally, PPARα inhibition decreased the phosphorylation level of 5'-adenosine monophosphate-activated protein kinase, indicating lower mitochondrial fatty acid oxidation. In summary, SCD1 ablation/inhibition decreased cardiac lipid content independently of the action of PPARα by reducing lipogenesis and activating lipolysis. The present data suggest that SCD1 is an important component in maintaining proper cardiac lipid metabolism.


Assuntos
Coração/fisiologia , Metabolismo dos Lipídeos/fisiologia , Lipídeos/fisiologia , Lipólise/fisiologia , PPAR gama/metabolismo , Estearoil-CoA Dessaturase/deficiência , Monofosfato de Adenosina/metabolismo , Animais , Linhagem Celular , Ceramidas/metabolismo , Ácidos Graxos não Esterificados/metabolismo , Lipogênese/fisiologia , Camundongos , Camundongos Knockout , Miócitos Cardíacos/metabolismo , Oxirredução , Fosforilação/fisiologia , Triglicerídeos/metabolismo
7.
Postepy Hig Med Dosw (Online) ; 70(0): 644-53, 2016 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-27333934

RESUMO

The heart has a limited capacity for lipogenesis and de novo lipid synthesis. However, expression of lipogenic genes in cardiomyocytes is unexpectedly high. Recent studies showed that lipogenic genes are important factors regulating cardiac metabolism and function. Long chain fatty acids are a major source of ATP required for proper heart function, and under aerobic conditions, the heart derives 60-90% of the energy necessary for contractile function from fatty acid oxidation. On the other hand, cardiac lipid over-accumulation (e.g. ceramides, diacylglycerols) leads to heart dysfunction. Downregulation of the lipogenic genes' expression (e.g. sterol regulatory element binding protein 1, stearoyl-CoA desaturase, acetyl-CoA kwacarboxylase) decreased heart steatosis and cardiomyocyte apoptosis, improving systolic and diastolic function of the left ventricle. Lipogenic factors also regulate fatty acids and glucose utilization in the heart, underlining their important role in maintaining energetic homeostasis in pathological states. Fatty acid synthase, the enzyme catalyzing fatty acids de novo synthesis, affects cardiac calcium signaling through regulation of L-type calcium channel activity. Thus, a growing body of evidence suggests that the role of lipogenic genes in cardiomyocytes may be distinct from other tissues. Here, we review recent advances made in understanding the role of lipogenic genes in the control of heart metabolism and its involvement in the pathogenesis of lipotoxic cardiomyopathy.


Assuntos
Coração/fisiologia , Lipogênese , Mitocôndrias Cardíacas/metabolismo , Oxirredução , Animais , Canais de Cálcio Tipo L/metabolismo , Ácido Graxo Sintases , Ácidos Graxos/metabolismo , Expressão Gênica , Humanos , Estearoil-CoA Dessaturase/metabolismo
8.
Prog Lipid Res ; 57: 1-12, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25482956

RESUMO

Stearoyl-CoA desaturase (SCD), a central enzyme in lipid metabolism that synthesizes monounsaturated fatty acids, has been linked to tissue metabolism and body adiposity regulation. Recent studies showed that SCD has the ability to reprogram cardiac metabolism, thereby regulating heart function. In the heart, the lack of SCD1 enhances glucose transport and metabolism at the expense of fatty acid (FA) uptake and oxidation. The metabolic changes associated with SCD1 deficiency protect cardiac myocytes against both necrotic and apoptotic cell death and improve heart function. Furthermore, SCD4, a heart-specific isoform of SCD, is specifically repressed by leptin and the lack of SCD1 function in leptin-deficient ob/ob mice results in a decrease in the accumulation of neutral lipids and ceramide and improves the systolic and diastolic function of a failing heart. Large-population human studies showed that the plasma SCD desaturation index is positively associated with heart rate, and cardiometabolic risk factors are modulated by genetic variations in SCD1. The current findings indicate that SCD may be used to reprogram myocardial metabolism to improve cardiac function. Here, we review recent advances in understanding the role of SCD in the control of heart metabolism and its involvement in the pathogenesis of lipotoxic cardiomyopathies.


Assuntos
Coração/fisiologia , Estearoil-CoA Dessaturase/genética , Estearoil-CoA Dessaturase/metabolismo , Animais , Cardiomiopatias/genética , Cardiomiopatias/metabolismo , Cardiomiopatias/patologia , Ácidos Graxos/metabolismo , Glucose/metabolismo , Testes de Função Cardíaca , Humanos , Camundongos
9.
Am J Physiol Endocrinol Metab ; 304(12): E1348-58, 2013 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-23632628

RESUMO

Cardiac hypertrophy is accompanied by molecular remodeling that affects different cellular pathways, including fatty acid (FA) utilization. In the present study, we show that cardiac lipid metabolism is differentially regulated in response to physiological (endurance training) and pathological [abdominal aortic banding (AAB)] hypertrophic stimuli. Physiological hypertrophy was accompanied by an increased expression of lipogenic genes and the activation of sterol regulatory element-binding protein-1c and Akt signaling. Additionally, FA oxidation pathways regulated by AMP-activated protein kinase (AMPK) and peroxisome proliferator activated receptor-α (PPARα) were induced in trained hearts. Cardiac lipid content was not changed by physiological stimulation, underlining balanced lipid utilization in the trained heart. Moreover, pathological hypertrophy induced the AMPK-regulated oxidative pathway, whereas PPARα and expression of its downstream targets, i.e., acyl-CoA oxidase and carnitine palmitoyltransferase I, were not affected by AAB. In contrast, pathological hypertrophy leads to cardiac triglyceride (TG) and diacylglycerol (DAG) accumulation, although the expression of lipogenic genes and the levels of FA transport proteins (CD36 and FATP) were not changed or reduced compared with the sham group. A possible explanation for this phenomenon is a decrease in lipolysis, as evidenced by the increased content of adipose triglyceride lipase inhibitor G0S2, the increased phosphorylation of hormone-sensitive lipase at Ser(565), and the decreased protein levels of DAG lipase that attenuate TG and DAG contents. The increased TG and DAG accumulation observed in AAB-induced hypertrophy might have lipotoxic effects, thereby predisposing to cardiomyopathy and heart failure in the future.


Assuntos
Coração/fisiologia , Hipertrofia Ventricular Esquerda/genética , Hipertrofia Ventricular Esquerda/fisiopatologia , Lipogênese/genética , Condicionamento Físico Animal/fisiologia , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Ácidos Graxos/metabolismo , Regulação da Expressão Gênica/fisiologia , Hipertrofia Ventricular Esquerda/diagnóstico por imagem , Lipase/genética , Lipase/metabolismo , Lipogênese/fisiologia , Masculino , PPAR alfa/genética , PPAR alfa/metabolismo , Resistência Física/fisiologia , Distribuição Aleatória , Ratos , Ratos Wistar , Ultrassonografia , Regulação para Cima/fisiologia
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