RESUMO
Stearoyl-CoA desaturase (SCD) is a lipogenic enzyme that catalyzes formation of the first double bond in the carbon chain of saturated fatty acids. Four isoforms of SCD have been identified in mice, the most poorly characterized of which is SCD4, which is cardiac-specific. In the present study, we investigated the role of SCD4 in systemic and cardiac metabolism. We used wildtype (WT) and global SCD4 knockout mice that were fed standard laboratory chow or a high-fat diet (HFD). SCD4 deficiency reduced body adiposity and decreased hyperinsulinemia and hypercholesterolemia in HFD-fed mice. The loss of SCD4 preserved heart morphology in the HFD condition. Lipid accumulation decreased in the myocardium in SCD4-deficient mice and in HL-1 cardiomyocytes with knocked out Scd4 expression. This was associated with an increase in the rate of lipolysis and, more specifically, adipose triglyceride lipase (ATGL) activity. Possible mechanisms of ATGL activation by SCD4 deficiency include lower protein levels of the ATGL inhibitor G0S2 and greater activation by protein kinase A under lipid overload conditions. Moreover, we observed higher intracellular Ca2+ levels in HL-1 cells with silenced Scd4 expression. This may explain the activation of protein kinase A in response to higher Ca2+ levels. Additionally, the loss of SCD4 inhibited mitochondrial enlargement, NADH overactivation, and reactive oxygen species overproduction in the heart in HFD-fed mice. In conclusion, SCD4 deficiency activated lipolysis, resulting in a reduction of cardiac steatosis, prevented the induction of left ventricular hypertrophy, and reduced reactive oxygen species levels in the heart in HFD-fed mice.
RESUMO
An interview with James M. Ntambi, professor of biochemistry and the Katherine Berns Van Donk Steenbock Professor in Nutrition, College of Agricultural and Life Sciences, at the University of Wisconsin-Madison, took place via Zoom in April 2022. He was interviewed by Patrick J. Stover, director of the Institute for Advancing Health through Agriculture and professor of nutrition and biochemistry and biophysics at Texas A&M University. Dr. James Ntambi is a true pioneer in the field of nutritional biochemistry. He was among the very first to discover and elucidate the role that diet and nutrients play in regulating metabolism through changes in the expression of metabolic genes, focusing on the de novo lipogenesis pathways. As an African immigrant from Uganda, his love of science and his life experiences in African communities suffering from severe malnutrition molded his scientific interests at the interface of biochemistry and nutrition. Throughout his career, he has been an academic role model, a groundbreaking nutrition scientist, and an educator. His commitment to experiential learning through the many study-abroad classes he has hosted in Uganda has provided invaluable context for American students in nutrition. Dr. Ntambi's passion for education and scientific discovery is his legacy, and the field of nutrition has benefited enormously from his unique perspectives and contributions to science that are defined by his scientific curiosity, his generosity to his students and colleagues, and his life experiences. The following is an edited transcript.
Assuntos
Agricultura , Bioquímica , Ciências da Nutrição , Humanos , Agricultura/história , Metabolismo/genética , Ciências da Nutrição/história , Estado Nutricional , Uganda , Estados Unidos , Wisconsin , População Africana , Desnutrição/genética , Desnutrição/metabolismo , Bioquímica/históriaRESUMO
Obesity is a major risk factor for type 2 diabetes, coronary heart disease, and strok. These diseases are associated with profound alterations in gene expression in metabolic tissues. Epigenetic-mediated regulation of gene expression is one mechanism through which environmental factors, such as diet, modify gene expression and disease predisposition. However, epigenetic control of gene expression in obesity and insulin resistance is not fully characterized. We discovered that liver-specific stearoyl-CoA desaturase-1 (Scd1) knockout mice (LKO) fed a high-carbohydrate low-fat diet exhibit dramatic changes in hepatic gene expression and metabolites of the folate cycle and one-carbon metabolism respectively for the synthesis of S-adenosylmethionine (SAM). LKO mice show an increased ratio of S-adenosylmethionine to S-adenosylhomocysteine, a marker for increased cellular methylation capacity. Furthermore, expression of DNA and histone methyltransferase genes is up-regulated while the mRNA and protein levels of the non-DNA methyltransferases including phosphatidylethanolamine methyltransferase (PEMT), Betaine homocysteine methyltransferase (Bhmt), and the SAM-utilizing enzymes such as glycine-N-methyltransferase (Gnmt) and guanidinoacetate methyltransferase (Gamt) are generally down-regulated. Feeding LKO mice a high carbohydrate diet supplemented with triolein, but not tristearin, and increased endogenous hepatic synthesis of oleate but not palmitoleate in Scd1 global knockout mice normalized one carbon gene expression and metabolite levels. Additionally, changes in one carbon gene expression are independent of the PGC-1α-mediated ER stress response previously reported in the LKO mice. Together, these results highlight the important role of oleate in maintaining one-carbon cycle homeostasis and point to observed changes in one-carbon metabolism as a novel mediator of the Scd1 deficiency-induced liver phenotype.
Assuntos
Diabetes Mellitus Tipo 2 , Ácido Oleico , Camundongos , Animais , Ácido Oleico/metabolismo , S-Adenosilmetionina/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Fígado/metabolismo , Carboidratos , Camundongos Knockout , Obesidade/metabolismo , Carbono/metabolismo , Fosfatidiletanolamina N-Metiltransferase/metabolismoRESUMO
Obesity and the metabolic syndrome are global public health problems. Obesity is currently a worldwide epidemic and public health burden that increases the risk for developing insulin resistance and several chronic diseases such as diabetes, cardiovascular disease and non-alcoholic fatty liver disease. The multifactorial causes of obesity include several genetic, dietary and lifestyle variables that together result in an imbalance between energy intake and energy expenditure. Dietary approaches to limit fat intake are commonly prescribed to achieve the hypocaloric conditions necessary for weight loss. But dietary fat restriction is often accompanied by increased carbohydrate intake, which can dramatically increase endogenous fatty acid synthesis depending upon carbohydrate composition. Since both dietary and endogenously synthesized fatty acids contribute to the whole-body fatty acid pool, obesity can therefore result from excessive fat or carbohydrate consumption.
Assuntos
Hepatopatia Gordurosa não Alcoólica , Estearoil-CoA Dessaturase , Humanos , Estearoil-CoA Dessaturase/genética , Lipogênese , Fígado/metabolismo , Obesidade/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Ácidos Graxos/metabolismo , CarboidratosRESUMO
New blood vessel formation is a key component of the cardiac repair process after myocardial infarction (MI). Hypoxia following MI is a major driver of angiogenesis in the myocardium. Hypoxia-inducible factor 1α (HIF1α) is the key regulator of proangiogenic signaling. The present study found that stearoyl-CoA desaturase (SCD) significantly contributed to the induction of angiogenesis in the hypoxic myocardium independently of HIF1α expression. The pharmacological inhibition of SCD activity in HL-1 cardiomyocytes and SCD knockout in an animal model disturbed the expression and secretion of proangiogenic factors including vascular endothelial growth factor-A, proinflammatory cytokines (interleukin-1ß, interleukin-6, tumor necrosis factor α, monocyte chemoattractant protein-1, and Rantes), metalloproteinase-9, and platelet-derived growth factor in ischemic cardiomyocytes. These disturbances affected the proangiogenic potential of ischemic cardiomyocytes after SCD depletion. Together with the most abundant SCD1 isoform, the heart-specific SCD4 isoform emerged as an important regulator of new blood vessel formation in the murine post-MI myocardium. We also provide evidence that SCD shapes energy metabolism of the ischemic heart by maintaining the shift from fatty acids to glucose as the substrate that is used for adenosine triphosphate production. Furthermore, we propose that the regulation of the proangiogenic properties of hypoxic cardiomyocytes by key modulators of metabolic signaling such as adenosine monophosphate kinase, protein kinase B (AKT), and peroxisome-proliferator-activated receptor-γ coactivator 1α/peroxisome proliferator-activated receptor α depends on SCD to some extent. Thus, our results reveal a novel mechanism that links SCD to cardiac repair processes after MI.
Assuntos
Infarto do Miocárdio , Estearoil-CoA Dessaturase , Monofosfato de Adenosina/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Quimiocina CCL2/metabolismo , Quimiocina CCL5/metabolismo , Metabolismo Energético , Ácidos Graxos/metabolismo , Glucose/metabolismo , Hipóxia/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Camundongos , Infarto do Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , PPAR alfa/metabolismo , Fator de Crescimento Derivado de Plaquetas/metabolismo , Isoformas de Proteínas/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Estearoil-CoA Dessaturase/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
Stearoyl-CoA desaturase-1 (SCD1) catalyzes the rate-liming step of monounsaturated fatty acid biosynthesis and is a key regulator of systemic glucose metabolism. Mice harboring either a global (GKO) or liver-specific deletion (LKO) of Scd1 display enhanced insulin signaling and whole-body glucose uptake. Additionally, GKO and LKO mice are protected from high-carbohydrate diet-induced obesity. Given that high-carbohydrate diets can lead to chronic metabolic diseases such as obesity, diabetes, and hepatic steatosis, it is critical to understand how Scd1 deficiency confers metabolically beneficial phenotypes. Here we show that insulin-like growth factor-binding protein 1 (IGFBP1), a hepatokine that has been reported to enhance insulin signaling, is significantly elevated in the liver and plasma of GKO and LKO mice fed a low-fat high-carbohydrate diet. We also observed that the expression of hepatic Igfbp1 is regulated by oleic acid (18:1n9), a product of SCD1, through the mTORC1-FGF21 axis both in vivo and in vitro.
Assuntos
Proteína 1 de Ligação a Fator de Crescimento Semelhante à Insulina , Alvo Mecanístico do Complexo 1 de Rapamicina , Ácido Oleico , Estearoil-CoA Dessaturase , Animais , Camundongos , Insulina/metabolismo , Fígado/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Obesidade/metabolismo , Ácido Oleico/metabolismo , Estearoil-CoA Dessaturase/genética , Estearoil-CoA Dessaturase/metabolismo , Proteína 1 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Carboidratos da Dieta/administração & dosagemRESUMO
Increased carbohydrate consumption increases hepatic de novo lipogenesis, which has been linked to the development of chronic metabolic diseases, including obesity, hepatic steatosis, and insulin resistance. Stearoyl CoA desaturase 1 (SCD1) is a critical lipogenic enzyme that catalyzes the synthesis of two monounsaturated fatty acids, oleate and palmitoleate, from the saturated fatty acids stearate and palmitate, respectively. SCD1-deficient mouse models are protected against diet-induced adiposity, hepatic steatosis, and hyperglycemia. However, the mechanism of this protection by SCD1 deficiency is unclear. Using liver-specific SCD1 knockout (LKO) mice fed a high-carbohydrate, low-fat diet, we show that hepatic SCD1 deficiency increases systemic glucose uptake. Hepatic SCD1 deficiency enhanced glucose transporter type 1 (GLUT1) expression in the liver and also up-regulated GLUT4 and adiponectin expression in adipose tissue. The enhanced glucose uptake correlated with increased liver expression and elevated plasma levels of fibroblast growth factor 21 (FGF21), a hepatokine known to increase systemic insulin sensitivity and regulate whole-body lipid metabolism. Feeding LKO mice a triolein-supplemented but not tristearin-supplemented high-carbohydrate, low-fat diet reduced FGF21 expression and plasma levels. Consistently, SCD1 inhibition in primary hepatocytes induced FGF21 expression, which was repressed by treatment with oleate but not palmitoleate. Moreover, deletion of the transcriptional coactivator PPARγ coactivator 1α (PGC-1α) reduced hepatic and plasma FGF21 and white adipocyte tissue-specific GLUT4 expression and raised plasma glucose levels in LKO mice. These results suggest that hepatic oleate regulates glucose uptake in adipose tissue either directly or partially by modulating the hepatic PGC-1α-FGF21 axis.
Assuntos
Tecido Adiposo/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Glucose/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Estearoil-CoA Dessaturase/genética , Adiponectina/sangue , Adiposidade , Animais , Metabolismo dos Carboidratos , Dieta , Ácidos Graxos Monoinsaturados/metabolismo , Fígado Gorduroso/metabolismo , Insulina/metabolismo , Metabolismo dos Lipídeos , Lipogênese , Fígado/metabolismo , Masculino , Camundongos , Camundongos Knockout , Ácido Oleico/farmacologia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Estearoil-CoA Dessaturase/metabolismoRESUMO
Stearoyl-CoA desaturase (SCD) is a rate-limiting enzyme that catalyzes the synthesis of monounsaturated fatty acids. It plays an important role in regulating skeletal muscle metabolism. Lack of the SCD1 gene increases the rate of fatty acid ß-oxidation through activation of the AMP-activated protein kinase (AMPK) pathway and the upregulation of genes that are related to fatty acid oxidation. The mechanism of AMPK activation under conditions of SCD1 deficiency has been unclear. In the present study, we found that the ablation/inhibition of SCD1 led to AMPK activation in skeletal muscle through an increase in AMP levels whereas muscle-specific SCD1 overexpression decreased both AMPK phosphorylation and the adenosine monophosphate/adenosine triphosphate (AMP/ATP) ratio. Changes in AMPK phosphorylation that were caused by SCD1 down- and upregulation affected NAD+ levels following changes in NAD+ -dependent deacetylase sirtuin-1 (SIRT1) activity and histone 3 (H3K9) acetylation and methylation status. Moreover, mice with muscle-targeted overexpression of SCD1 were more susceptible to high-fat diet-induced lipid accumulation and the development of insulin resistance compared with wild-type mice. These data show that SCD1 is involved in nucleotide (ATP and NAD+ ) metabolism and suggest that the SCD1-dependent regulation of muscle steatosis and insulin sensitivity are mediated by cooperation between AMPK- and SIRT1-regulated pathways. Altogether, the present study reveals a novel mechanism that links SCD1 with the maintenance of metabolic homeostasis and insulin sensitivity in skeletal muscle.
Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Nucleotídeos de Adenina/metabolismo , Histonas/metabolismo , Músculo Esquelético/metabolismo , Sirtuína 1/metabolismo , Estearoil-CoA Dessaturase/metabolismo , Proteínas Quinases Ativadas por AMP/genética , Acetilação , Animais , Linhagem Celular , Dieta Hiperlipídica , Regulação para Baixo , Regulação da Expressão Gênica , Histonas/genética , Humanos , Resistência à Insulina , Masculino , Camundongos , Camundongos Knockout , Fibras Musculares de Contração Rápida/metabolismo , Fibras Musculares de Contração Lenta/metabolismo , Sirtuína 1/genética , Estearoil-CoA Dessaturase/genéticaRESUMO
In mouse, there are four stearoyl-CoA desaturase isoforms (SCD1-4) that catalyze the synthesis of monounsaturated fatty acids. Previously, we have shown that mice harboring a whole body deletion of the SCD1 isoform (SCD1KO) are protected from diet and genetically induced adiposity. Here, we report that global deletion of the SCD2 isoform (SCD2KO) provides a similar protective effect against the onset of both high-fat diet (HFD) and high-carbohydrate diet (HCD) induced adiposity. After 10 weeks of HFD feeding or 6 weeks of HCD feeding, SCD2KO mice failed to gain weight and had decreased fat mass. On HFD, SCD2KO mice remained glucose and insulin tolerant. Lastly, the markers for energy expenditure, UCP1 and PGC-1α, were increased in the brown adipose tissue of HFD fed SCD2KO mice.
Assuntos
Adiposidade , Dieta da Carga de Carboidratos/efeitos adversos , Dieta Hiperlipídica/efeitos adversos , Deleção de Genes , Obesidade/genética , Estearoil-CoA Dessaturase/genética , Animais , Metabolismo Energético , Feminino , Glucose/metabolismo , Insulina/metabolismo , Masculino , Camundongos , Camundongos Knockout , Obesidade/etiologia , Obesidade/metabolismo , Fatores de Proteção , Estearoil-CoA Dessaturase/deficiência , Estearoil-CoA Dessaturase/metabolismoRESUMO
Growth factor receptor-binding protein 10 (GRB10) is a well-known adaptor protein and a recently identified substrate of the mammalian target of rapamycin (mTOR). Depletion of GRB10 increases insulin sensitivity and overexpression suppresses PI3K/Akt signaling. Because the major reason for the limited efficacy of PI3K/Akt-targeted therapies in prostate cancer (PCa) is loss of mTOR-regulated feedback suppression, it is therefore important to assess the functional importance and regulation of GRB10 under these conditions. On the basis of these background observations, we explored the status and functional impact of GRB10 in PCa and found maximum expression in phosphatase and tensin homolog (PTEN)-deficient PCa. In human PCa samples, GRB10 inversely correlated with PTEN and positively correlated with pAKT levels. Knockdown of GRB10 in nontumorigenic PTEN null mouse embryonic fibroblasts and tumorigenic PCa cell lines reduced Akt phosphorylation and selectively activated a panel of receptor tyrosine kinases. Similarly, overexpression of GRB10 in PTEN wild-type PCa cell lines accelerated tumorigenesis and induced Akt phosphorylation. In PTEN wild-type PCa, GRB10 overexpression promoted mediated PTEN interaction and degradation. PI3K (but not mTOR) inhibitors reduced GRB10 expression, suggesting primarily PI3K-driven regulation of GRB10. In summary, our results suggest that GRB10 acts as a major downstream effector of PI3K and has tumor-promoting effects in prostate cancer.-Khan, M. I., Al Johani, A., Hamid, A., Ateeq, B., Manzar, N., Adhami, V. M., Lall, R. K., Rath, S., Sechi, M., Siddiqui, I. A., Choudhry, H., Zamzami, M. A., Havighurst, T. C., Huang, W., Ntambi, J. M., Mukhtar, H. Proproliferatve function of adaptor protein GRB10 in prostate carcinoma.
Assuntos
Proteína Adaptadora GRB10/metabolismo , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Animais , Carcinógenos/antagonistas & inibidores , Carcinógenos/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/genética , Proliferação de Células/fisiologia , Fibroblastos/citologia , Fibroblastos/metabolismo , Proteína Adaptadora GRB10/antagonistas & inibidores , Proteína Adaptadora GRB10/genética , Técnicas de Silenciamento de Genes , Humanos , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Camundongos , Modelos Biológicos , PTEN Fosfo-Hidrolase/deficiência , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Neoplasias da Próstata/genética , RNA Mensageiro , Transdução de SinaisRESUMO
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.
Assuntos
Regulação para Baixo , Regulação Enzimológica da Expressão Gênica , Metabolismo dos Lipídeos , Miocárdio/metabolismo , Estearoil-CoA Dessaturase/biossíntese , Tireotropina/metabolismo , Tiroxina/metabolismo , Animais , Camundongos , Camundongos Knockout , Estearoil-CoA Dessaturase/genética , Tireotropina/genética , Tiroxina/genéticaRESUMO
Stearoyl-CoA Desaturase-2 (SCD2) is a member of the Stearoyl-CoA Desaturase (SCD) family of enzymes that catalyze the rate-limiting step in monounsaturated fatty acid (MUFA) synthesis. The MUFAs palmitoleoyl-CoA (16:1n7) and oleoyl-CoA (18:1n9) are the major products of SCD2. Palmitoleoyl-CoA and oleoyl-CoA have various roles, from being a source of energy to signaling molecules. Under normal feeding conditions, SCD2 is ubiquitously expressed and is the predominant SCD isoform in the brain. However, obesogenic diets highly induce SCD2 in adipose tissue, lung, and kidney. Here we provide a comprehensive review of SCD2 in mouse development, metabolism, and various diseases, such as obesity, chronic kidney disease, Alzheimer's disease, multiple sclerosis, and Parkinson's disease. In addition, we show that bone mineral density is decreased in SCD2KO mice under high-fat feeding conditions and that SCD2 is not required for preadipocyte differentiation or the expression of PPARγ in vivo despite being required in vitro.
Assuntos
Adipócitos/enzimologia , Diferenciação Celular , Ácidos Graxos Monoinsaturados/metabolismo , Doenças Neurodegenerativas/enzimologia , Obesidade/enzimologia , Insuficiência Renal Crônica/enzimologia , Estearoil-CoA Dessaturase/metabolismo , Acil Coenzima A/biossíntese , Acil Coenzima A/genética , Animais , Dieta Hiperlipídica/efeitos adversos , Camundongos , Camundongos Knockout , Doenças Neurodegenerativas/genética , Obesidade/induzido quimicamente , Obesidade/genética , Obesidade/metabolismo , Palmitoil Coenzima A/biossíntese , Palmitoil Coenzima A/genética , Insuficiência Renal Crônica/genética , Estearoil-CoA Dessaturase/genéticaRESUMO
BACKGROUND & AIMS: The enzyme stearoyl-coenzyme A desaturase 1 (SCD or SCD1) produces monounsaturated fatty acids by introducing double bonds into saturated bonds between carbons 9 and 10, with oleic acid as the main product. SCD1 is present in the intestinal epithelium, and fatty acids regulate cell proliferation, so we investigated the effects of SCD1-induced production of oleic acid in enterocytes in mice. METHODS: We generated mice with disruption of Scd1 selectively in the intestinal epithelium (iScd1-/- mice) on a C57BL/6 background; iScd1+/+ mice were used as controls. We also generated iScd1-/-ApcMin/+ mice and studied cancer susceptibility. Mice were fed a chow, oleic acid-deficient, or oleic acid-rich diet. Intestinal tissues were collected and analyzed by histology, reverse transcription quantitative polymerase chain reaction, immunohistochemistry, and mass spectrometry, and tumors were quantified and measured. RESULTS: Compared with control mice, the ileal mucosa of iScd1-/- mice had a lower proportion of palmitoleic (C16:1 n-7) and oleic acids (C18:1 n-9), with accumulation of stearic acid (C18:0); this resulted a reduction of the Δ9 desaturation ratio between monounsaturated (C16:1 n-7 and C18:1 n-9) and saturated (C16:0 and C18:0) fatty acids. Ileal tissues from iScd1-/- mice had increased expression of markers of inflammation activation and crypt proliferative genes compared with control mice. The iScd1-/-ApcMin/+ mice developed more and larger tumors than iScd1+/+ApcMin/+ mice. iScd1-/-ApcMin/+ mice fed the oleic acid-rich diet had reduced intestinal inflammation and significantly lower tumor burden compared with mice fed a chow diet. CONCLUSIONS: In studies of mice, we found intestinal SCD1 to be required for synthesis of oleate in the enterocytes and maintenance of fatty acid homeostasis. Dietary supplementation with oleic acid reduces intestinal inflammation and tumor development in mice.
Assuntos
Gorduras Insaturadas na Dieta/administração & dosagem , Enterite/etiologia , Mucosa Intestinal/enzimologia , Neoplasias Intestinais/etiologia , Ácido Oleico/administração & dosagem , Estearoil-CoA Dessaturase/fisiologia , Animais , Feminino , Mucosa Intestinal/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ácido Oleico/metabolismo , Carga TumoralRESUMO
Stearoyl-CoA desaturase 1 (SCD1), a lipogenic enzyme that adds a double bond at the delta 9 position of stearate (C18: 0) and palmitate (C16: 0), has been proven to be important in the development of obesity. Mice with skin-specific deficiency of SCD1 (SKO) display increased whole-body energy expenditure, which is protective against adiposity from a high-fat diet because it improves glucose clearance, insulin sensitivity, and hepatic steatosis. Of note, these mice also display elevated levels of the "pro-inflammatory" plasma interleukin-6 (IL-6). In whole skin of SKO mice, IL-6 mRNA levels are increased, and protein expression is evident in hair follicle cells and in keratinocytes. Recently, the well-known role of IL-6 in causing white adipose tissue lipolysis has been linked to indirectly activating the gluconeogenic enzyme pyruvate carboxylase 1 in the liver, thereby increasing hepatic glucose production. In this study, we suggest that skin-derived IL-6 leads to white adipose tissue lipolysis, which contributes to the lean phenotype of SKO mice without the incidence of meta-inflammation that is associated with IL-6 signaling.
Assuntos
Interleucina-6/metabolismo , Pele/metabolismo , Estearoil-CoA Dessaturase/deficiência , Tecido Adiposo Branco/metabolismo , Adiposidade , Animais , Dieta Hiperlipídica/efeitos adversos , Ácidos Graxos/metabolismo , Gluconeogênese , Folículo Piloso/citologia , Folículo Piloso/metabolismo , Interleucina-6/genética , Queratinócitos/metabolismo , Lipólise , Fígado/metabolismo , Macrófagos/citologia , Masculino , Camundongos , Camundongos Knockout , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Pele/citologia , Estearoil-CoA Dessaturase/genética , Magreza/genética , Magreza/metabolismo , Distribuição TecidualRESUMO
Uncoupling protein-1 (UCP1) facilitates thermogenesis in brown and beige adipocytes and can promote energy expenditure by decreasing mitochondrial respiratory efficiency. Defects in UCP1 and brown adipose tissue thermogenesis subject animals to chronic cold stress and elicit compensatory responses to generate heat. How UCP1 regulates white adipose tissue (WAT) lipid biology and tissue crosstalk is not completely understood. Here, we probed the effect of UCP1 deficiency on FA metabolism in inguinal and epididymal WAT and investigated how these metabolic perturbations influence hepatic lipid homeostasis. We report that at standard housing temperature (21°C), loss of UCP1 induces inguinal WAT de novo lipogenesis through transcriptional activation of the lipogenic gene program and elevated GLUT4. Inguinal adipocyte hyperplasia and depot expansion accompany the increase in lipid synthesis. We also found that UCP1 deficiency elevates adipose stearoyl-CoA desaturase gene expression, and increased inguinal WAT lipolysis supports the transport of adipose-derived palmitoleate (16:1n7) to the liver and hepatic triglyceride accumulation. The observed WAT and liver phenotypes were resolved by housing animals at thermoneutral housing (30°C). These data illustrate depot-specific responses to impaired BAT thermogenesis and communication between WAT and liver in UCP1-/- mice.
Assuntos
Tecido Adiposo/metabolismo , Ácidos Graxos Monoinsaturados/metabolismo , Fígado/metabolismo , Proteína Desacopladora 1/deficiência , Proteína Desacopladora 1/metabolismo , Tecido Adiposo/química , Animais , Ácidos Graxos Monoinsaturados/química , Fígado/química , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Estearoil-CoA Dessaturase/genética , Estearoil-CoA Dessaturase/metabolismoRESUMO
After crossing floxed stearoyl-CoA desaturase-1 (Scd1fl/fl) mice with LDL receptor-null (ldlr-/-) mice, and then Villin Cre (VilCre) mice, enterocyte Scd1 expression in Scd1fl/fl/ldlr-/-/VilCre mice was reduced 70%. On Western diet (WD), Scd1fl/fl/ldlr-/- mice gained more weight than Scd1fl/fl/ldlr-/-/VilCre mice (P < 0.0023). On WD, jejunum levels of lysophosphatidylcholine (LysoPC) 18:1 and lysophosphatidic acid (LPA) 18:1 were significantly less in Scd1fl/fl/ldlr-/-/VilCre compared with Scd1fl/fl/ldlr-/- mice (P < 0.0004 and P < 0.026, respectively). On WD, Scd1fl/fl/ldlr-/-/VilCre mice compared with Scd1fl/fl/ldlr-/- mice had lower protein levels of lipopolysaccharide-binding protein (LBP), cluster of differentiation 14 (CD14), toll-like receptor 4 (TLR4), and myeloid differentiation factor-88 (MyD88) in enterocytes and plasma, and less dyslipidemia and systemic inflammation. Adding a concentrate of tomatoes transgenic for the apoA-I mimetic peptide 6F (Tg6F) to WD resulted in reduced enterocyte protein levels of LBP, CD14, TLR4, and MyD88 in Scd1fl/fl/ldlr-/- mice similar to that seen in Scd1fl/fl/ldlr-/-/VilCre mice. Adding LysoPC 18:1 to WD did not reverse the effects of enterocyte Scd1 knockdown. Adding LysoPC 18:1 (but not LysoPC 18:0) to chow induced jejunum Scd1 expression and increased dyslipidemia and plasma serum amyloid A and interleukin 6 levels in Scd1fl/fl/ldlr-/- mice, but not in Scd1fl/fl/ldlr-/-/VilCre mice. We conclude that enterocyte Scd1 is partially responsible for LysoPC 18:1- and WD-induced dyslipidemia and inflammation in ldlr-/- mice.
Assuntos
Enterócitos/enzimologia , Deleção de Genes , Receptores de LDL/deficiência , Receptores de LDL/genética , Estearoil-CoA Dessaturase/metabolismo , Proteínas de Fase Aguda/metabolismo , Animais , Peso Corporal , Proteínas de Transporte/metabolismo , HDL-Colesterol/sangue , Dislipidemias/enzimologia , Dislipidemias/genética , Dislipidemias/metabolismo , Feminino , Regulação Enzimológica da Expressão Gênica , Técnicas de Silenciamento de Genes , Jejuno/metabolismo , Receptores de Lipopolissacarídeos/metabolismo , Lisofosfatidilcolinas/metabolismo , Masculino , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Fator 88 de Diferenciação Mieloide/metabolismo , Estearoil-CoA Dessaturase/deficiência , Estearoil-CoA Dessaturase/genética , Receptor 4 Toll-Like/metabolismoRESUMO
Δ9-Desaturases are central enzymes in unsaturated fatty acid synthesis regulated at the transcriptional and mRNA levels and by proteasomal degradation. A new study by Murakami et al. uncovers a novel regulatory pathway in which an N-terminal di-proline motif in the Drosophila Δ9-desaturase mediates protein degradation by a calcium-dependent cysteine protease in response to unsaturated fatty acids. This study provides new details of desaturase regulation with therapeutic implications for the treatment of metabolic syndrome.
Assuntos
Drosophila , Ácidos Graxos Dessaturases , Animais , Ácidos Graxos , Prolina , Estearoil-CoA DessaturaseRESUMO
BACKGROUND & AIMS: Stearoyl-CoA desaturase (SCD) synthesizes monounsaturated fatty acids (MUFAs) and has been associated with the development of metabolic syndrome, tumorigenesis, and stem cell characteristics. We investigated whether and how SCD promotes liver fibrosis and tumor development in mice. METHODS: Rodent primary hepatic stellate cells (HSCs), mouse liver tumor-initiating stem cell-like cells (TICs), and human hepatocellular carcinoma (HCC) cell lines were exposed to Wnt signaling inhibitors and changes in gene expression patterns were analyzed. We assessed the functions of SCD by pharmacologic and conditional genetic manipulation in mice with hepatotoxic or cholestatic induction of liver fibrosis, orthotopic transplants of TICs, or liver tumors induced by administration of diethyl nitrosamine. We performed bioinformatic analyses of SCD expression in HCC vs nontumor liver samples collected from patients, and correlated levels with HCC stage and patient mortality. We performed nano-bead pull-down assays, liquid chromatography-mass spectrometry, computational modeling, and ribonucleoprotein immunoprecipitation analyses to identify MUFA-interacting proteins. We examined the effects of SCD inhibition on Wnt signaling, including the expression and stability of low-density lipoprotein-receptor-related proteins 5 and 6 (LRP5 and LRP6), by immunoblot and quantitative polymerase chain reaction analyses. RESULTS: SCD was overexpressed in activated HSC and HCC cells from patients; levels of SCD messenger RNA (mRNA) correlated with HCC stage and patient survival time. In rodent HSCs and TICs, the Wnt effector ß-catenin increased sterol regulatory element binding protein 1-dependent transcription of Scd, and ß-catenin in return was stabilized by MUFAs generated by SCD. This loop required MUFA inhibition of binding of Ras-related nuclear protein 1 (Ran1) to transportin 1 and reduced nuclear import of elav-like protein 1 (HuR), increasing cytosolic levels of HuR and HuR-mediated stabilization of mRNAs encoding LRP5 and LRP6. Genetic disruption of Scd and pharmacologic inhibitors of SCD reduced HSC activation and TIC self-renewal and attenuated liver fibrosis and tumorigenesis in mice. Conditional disruption of Scd2 in activated HSCs prevented growth of tumors from TICs and reduced the formation of diethyl nitrosamine-induced liver tumors in mice. CONCLUSIONS: In rodent HSCs and TICs, we found SCD expression to be regulated by Wnt-ß-catenin signaling, and MUFAs produced by SCD provided a forward loop to amplify Wnt signaling via stabilization of Lrp5 and Lrp6 mRNAs, contributing to liver fibrosis and tumor growth. SCD expressed by HSCs promoted liver tumor development in mice. Components of the identified loop linking HSCs and TICs might be therapeutic targets for liver fibrosis and tumors.
Assuntos
Carcinoma Hepatocelular/metabolismo , Ácidos Graxos Monoinsaturados/metabolismo , Cirrose Hepática/metabolismo , Neoplasias Hepáticas/metabolismo , Estearoil-CoA Dessaturase/genética , Estearoil-CoA Dessaturase/metabolismo , Via de Sinalização Wnt/genética , Animais , Carcinoma Hepatocelular/induzido quimicamente , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Estudos de Casos e Controles , Linhagem Celular Tumoral , Colestase/complicações , Dietilnitrosamina , Proteína Semelhante a ELAV 1/metabolismo , Células Estreladas do Fígado , Humanos , Cirrose Hepática/etiologia , Cirrose Hepática/patologia , Neoplasias Hepáticas/induzido quimicamente , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Proteína-5 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Proteína-5 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Masculino , Camundongos , Estadiamento de Neoplasias , Transplante de Neoplasias , Células-Tronco Neoplásicas , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Taxa de Sobrevida , Transcrição Gênica , beta Catenina/metabolismo , beta Carioferinas/metabolismo , Proteína ran de Ligação ao GTP/metabolismoRESUMO
Cardiovascular disease is a primary cause of mortality worldwide. Therefore, it is of major interest to identify sensitive molecular markers that predict cardiovascular events and point to therapeutic strategies that will increase lifespans. Dysregulated lipid metabolism is recognized as an established risk factor in cardiovascular diseases. However, it is still largely unknown which specific lipid molecular species reflect cardiovascular risk. In addition, understanding the whole lipidome signature in vascular pathophysiology is challenging. Recent advancements of mass-spectrometry allow researchers to detect each individual lipid species from unbiased small samples. In this review, we update the current research on lipidomic approaches in cardiovascular diseases.
Assuntos
Doenças Cardiovasculares/metabolismo , Lipídeos/análise , Metabolômica/métodos , Biomarcadores/análise , Pesquisa Biomédica/métodos , Pesquisa Biomédica/tendências , Doenças Cardiovasculares/diagnóstico , Humanos , Metabolismo dos Lipídeos , Reprodutibilidade dos Testes , Fatores de Risco , Sensibilidade e EspecificidadeRESUMO
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.