Effect of the ACAA1 Gene on Preadipocyte Differentiation in Sheep

Acetyl-CoA acyltransferase 1 (ACAA1) functions as a key regulator of fatty acid β-oxidation in peroxisomes by catalyzing the cleavage of 3-ketoacyl-CoA to acetyl-CoA and acyl-CoA, which participate in the extension and degradation of fatty acids. Thus, ACAA1 is an important regulator of lipid metabolism and plays an essential role in fatty acid oxidation and lipid metabolism. Our previous study findings revealed that ACAA1 is closely associated with the peroxisome proliferator-activated receptor (PPAR) signaling and fatty acid metabolism pathways, which are involved in fat deposition in sheep, leading to our hypothesis that ACAA1 may be involved in fat deposition by regulating lipid metabolism. However, the associated molecular mechanism remains unclear. In the present study, to assess the potential function of ACAA1 in sheep preadipocyte differentiation, we knocked down and overexpressed ACAA1 in sheep preadipocytes and evaluated the pattern of ACAA1 gene expression during preadipocyte differentiation by qRT-PCR. ACAA1 was significantly expressed in the early stage of adipocyte differentiation, and then its expression decreased. ACAA1 deficiency increased lipid accumulation and the triglyceride content and promoted sheep preadipocyte differentiation, whereas ACAA1 overexpression inhibited adipogenesis and decreased lipid accumulation and the triglyceride content. Simultaneously, we demonstrated that ACAA1 deficiency upregulated the expressions of the adipogenic marker genes PPARγ and C/EBPα in sheep preadipocytes, but ACAA1 overexpression inhibited the expressions of these markers, indicating that ACAA1 affects lipid metabolism by regulating adipogenic marker genes. Our results may promote a better understanding of the regulation of adipogenesis by ACAA1.

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Phosphorylation of Acetyl-CoA Carboxylase by AMPK Reduces Renal Fibrosis and Is Essential for the Anti-Fibrotic Effect of Metformin

Journal of the American Society of Nephrology ◽

10.1681/asn.2018010050 ◽

2018 ◽

Vol 29 (9) ◽

pp. 2326-2336 ◽

Cited By ~ 27

Author(s):

Mardiana Lee ◽

Marina Katerelos ◽

Kurt Gleich ◽

Sandra Galic ◽

Bruce E. Kemp ◽

...

Keyword(s):

Fatty Acid ◽

Epithelial Cells ◽

Lipid Accumulation ◽

Acid Oxidation ◽

Acetyl Coa Carboxylase ◽

Tubular Epithelial Cells ◽

Acetyl Coa ◽

Expression Of Genes ◽

Energy Sensing ◽

Unilateral Ureteric Obstruction

BackgroundExpression of genes regulating fatty acid metabolism is reduced in tubular epithelial cells from kidneys with tubulointerstitial fibrosis (TIF), thus decreasing the energy produced by fatty acid oxidation (FAO). Acetyl-CoA carboxylase (ACC), a target for the energy-sensing AMP-activating protein kinase (AMPK), is the major controller of the rate of FAO within cells. Metformin has a well described antifibrotic effect, and increases phosphorylation of ACC by AMPK, thereby increasing FAO.MethodsWe evaluated phosphorylation of ACC in cell and mouse nephropathy models, as well as the effects of metformin administration in mice with and without mutations that reduce ACC phosphorylation.ResultsReduced phosphorylation of ACC on the AMPK site Ser79 occurred in both tubular epithelial cells treated with folate to mimic cellular injury and in wild-type (WT) mice after induction of the folic acid nephropathy model. When this effect was exaggerated in mice with knock-in (KI) Ser to Ala mutations of the phosphorylation sites in ACC, lipid accumulation and fibrosis increased significantly compared with WT. The effect of ACC phosphorylation on fibrosis was confirmed in the unilateral ureteric obstruction model, which showed significantly increased lipid accumulation and fibrosis in the KI mice. Metformin use was associated with significantly reduced fibrosis and lipid accumulation in WT mice. In contrast, in the KI mice, the drug was associated with worsened fibrosis.ConclusionsThese data indicate that reduced phosphorylation of ACC after renal injury contributes to the development of TIF, and that phosphorylation of ACC is required for metformin’s antifibrotic action in the kidney.

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miR-135a-5p inhibits 3T3-L1 adipogenesis through activation of canonical Wnt/β-catenin signaling

Journal of Molecular Endocrinology ◽

10.1530/jme-14-0013 ◽

2014 ◽

Vol 52 (3) ◽

pp. 311-320 ◽

Cited By ~ 31

Author(s):

Chen Chen ◽

Yongdong Peng ◽

Yinglin Peng ◽

Jian Peng ◽

Siwen Jiang

Keyword(s):

Fatty Acid ◽

Fatty Acid Synthase ◽

Binding Protein ◽

Adipogenic Differentiation ◽

Transcriptional Regulators ◽

Marker Genes ◽

Preadipocyte Differentiation ◽

Fatty Acid Binding ◽

Canonical Wnt ◽

Adipogenic Marker

MicroRNAs are endogenous, conserved, and non-coding small RNAs that function as post-transcriptional regulators of fat development and adipogenesis. Adipogenic marker genes, such as CCAAT/enhancer binding protein α (Cebpa), peroxisome proliferator-activated receptor γ (Pparg), adipocyte fatty acid binding protein (Ap2), and fatty acid synthase (Fas), are regarded as the essential transcriptional regulators of preadipocyte differentiation and lipid storage in mature adipocytes. Canonical Wnt/β-catenin signaling is recognized as a negative molecular switch during adipogenesis. In the present work we found that miR-135a-5p is markedly downregulated during the process of 3T3-L1 preadipocyte differentiation. Overexpression of miR-135a-5p impairs the expressions of adipogenic marker genes as well as lipid droplet accumulation and triglyceride content, indicating the importance of miR-135a-5p for adipogenic differentiation and adipogenesis. Further studies show that miR-135a-5p directly targets adenomatous polyposis coli (Apc), contributes to the translocation of β-catenin from cytoplasm to nucleus, and then activates the expressions of cyclin D1 (Ccnd1) and Cmyc, indicating the induction of canonical Wnt/β-catenin signaling. In addition, inhibition of APC with siRNA exhibits the same effects as overexpression of miR-135a-5p. Our findings demonstrate that miR-135a-5p suppresses 3T3-L1 preadipocyte differentiation and adipogenesis through the activation of canonical Wnt/β-catenin signaling by directly targeting Apc. Taken together, these results offer profound insights into the adipogenesis mechanism and the development of adipose tissue.

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Preparation and characterization of soybean insoluble dietary fiber and its prebiotic effect on dyslipidemia and hepatic steatosis in high fat-fed C57BL/6J mice

Food & Function ◽

10.1039/d1fo01050f ◽

2021 ◽

Author(s):

Sainan Wang ◽

Wanling Sun ◽

Mohammed Sharif Swallah ◽

Khalid Amin ◽

Bo Lyu ◽

...

Keyword(s):

Fatty Acid ◽

Lipid Metabolism ◽

Dietary Fiber ◽

Lipid Accumulation ◽

Crystalline Cellulose ◽

Acid Oxidation ◽

Cellulose I ◽

High Fat ◽

Insoluble Dietary Fiber

Insoluble dietary fiber extracted from soybean residue had a loose and porous structure, polysaccharide groups, and typical crystalline cellulose I structure. It played a role in regulating lipid metabolism by promoting fatty acid oxidation and inhibiting lipid accumulation.

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

International Journal of Molecular Sciences ◽

10.3390/ijms22010109 ◽

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.

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Cinnamic Acid Ameliorates Nonalcoholic Fatty Liver Disease by Suppressing Hepatic Lipogenesis and Promoting Fatty Acid Oxidation

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2021/9561613 ◽

2021 ◽

Vol 2021 ◽

pp. 1-13

Author(s):

You Wu ◽

Minghui Wang ◽

Tao Yang ◽

Lingling Qin ◽

Yaomu Hu ◽

...

Keyword(s):

Fatty Acid ◽

Lipid Metabolism ◽

Liver Disease ◽

Fatty Acid Oxidation ◽

Cinnamic Acid ◽

Lipid Accumulation ◽

Fatty Liver Disease ◽

Acid Oxidation ◽

Hepatic Lipogenesis ◽

Nonalcoholic Fatty Liver

Background. Cinnamic acid (CA) has been shown to have many beneficial effects including regulating lipid metabolism and reducing obesity. However, its effect on nonalcoholic fatty liver disease (NAFDL) has not been investigated in detail. Thus, we performed this study in order to explore CA’s effect on hepatic lipid metabolism and the underlying mechanisms. Method. Oleic acid (OA) was used to induce lipid accumulation in HepG2 cells. After coincubation with CA, the cells were stained with oil red O and the triglyceride (TG) content was assessed. Key genes in lipogenesis and fatty acid oxidation pathways were tested. Additionally, db/db and wt/wt mice were divided into three groups, with the wt/wt mice representing the normal group and the db/db mice being divided into the NAFLD and CA groups. After 4 weeks of oral treatment, all mice were sacrificed and the blood lipid profile and liver tissues were assessed. Results. CA treatment reduced the lipid accumulation in HepG2 cells and in db/db mouse livers. ACLY, ACC, FAS, SCD1, PPARγ, and CD36 were significantly downregulated, while CPT1A, PGC1α, and PPARα were significantly upregulated. Conclusion. CA’s therapeutic effect on NAFLD may be attributed to its ability to lower hepatic lipid accumulation, which is mediated by suppression of hepatic lipogenesis and fatty acid intake, as well as increased fatty acid oxidation.

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ZNF300 stimulates fatty acid oxidation and alleviates hepatosteatosis through regulating PPARα

Biochemical Journal ◽

10.1042/bcj20180517 ◽

2019 ◽

Vol 476 (2) ◽

pp. 385-404 ◽

Cited By ~ 2

Author(s):

Feng-Juan Yan ◽

Yong-Jian Wang ◽

Shi-Ran Yan ◽

Jun Lu ◽

Yuan-Lin Zheng

Keyword(s):

Fatty Acid ◽

Lipid Metabolism ◽

Fatty Acid Oxidation ◽

Lipid Accumulation ◽

Dna Methyltransferase ◽

Methylation Status ◽

Acid Oxidation ◽

Hepatic Lipid ◽

Hepatic Lipid Accumulation ◽

Underlying Mechanisms

Abstract ZNF300 plays an important role in the regulation of HBV-related hepatocellular carcinoma. However, little is known about the role of ZNF300 in lipid metabolism and NAFLD. In the present study, we observed that ZNF300 expression was markedly decreased in free fatty acid (FFA)-induced fatty liver. Overexpressed ZNF300 alleviated hepatic lipid accumulation, whereas knockdown of ZNF300 enhanced the FFA-induced lipid accumulation. Investigations of the underlying mechanisms revealed that ZNF300 directly binds to and regulates the PPARα expression, thus promoting fatty acid oxidation. Furthermore, bisulfite pyrosequencing PCR (BSP) analysis identified the hypermethylation status of ZNF300 gene in FFA-treated hepatocytes. Importantly, the suppression of ZNF300 could be blocked by DNA methyltransferase inhibitor (5-azadC) or DNMT3a-siRNA. These results suggested that ZNF300 plays an important role in hepatic lipid metabolism via PPARα promoting fatty acid oxidation and this effect might be blocked by DNMT3a-mediated methylation of ZNF300. Therefore, in addition to ZNF300 expression levels, the methylation status of this gene also has a potential as a prognostic biomarker.

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Placental Accumulation of Triacylglycerols in Gestational Diabetes Mellitus and Its Association with Altered Fetal Growth are Related to the Differential Expressions of Proteins of Lipid Metabolism

Experimental and Clinical Endocrinology & Diabetes ◽

10.1055/a-1017-3182 ◽

2020 ◽

Cited By ~ 1

Author(s):

Manoharan Balachandiran ◽

Zachariah Bobby ◽

Gowri Dorairajan ◽

Sajini Elizabeth Jacob ◽

Victorraj Gladwin ◽

...

Keyword(s):

Diabetes Mellitus ◽

Fatty Acid ◽

Lipid Metabolism ◽

Gestational Diabetes ◽

Gestational Diabetes Mellitus ◽

Fetal Growth ◽

Fatty Acid Synthase ◽

Regulatory Element ◽

Acid Oxidation ◽

Placental Proteins

Abstract Introduction Gestational diabetes mellitus (GDM) exhibit altered placental lipid metabolism. The molecular basis of this altered metabolism is not clear. Altered placental expression of proteins of lipogenesis and fatty acid oxidation may be involved in the placental accumulation of triacylglycerols (TG). The present study was aimed at investigating the differential expressions of placental proteins related to lipid metabolism among GDM women in comparison with control pregnant women (CPW) and to correlate them with maternal and fetal lipid parameters as well as altered fetal growth. Materials and Methods Maternal blood, cord blood, and placental samples were collected from GDM and CPW. The biochemical parameters, glucose, lipid profile and free fatty acids (FFA) were measured. The placental TG content was measured. Differential placental expressions of proteins; phosphatidylinositol-3-kinase (PI3K) p85α, PI3K p110α,liver X receptor alpha (LXRα), sterol regulatory element binding protein1(SREBP1), fatty acid synthase (FAS), stearyl CoA desaturase1 (SCD1), lipoprotein lipase (LPL),Peroxisome proliferator-activated receptor (PPAR)α and PPARγ were analysed by western blotting and immunohistochemistry. Results Placental protein expressions of PI3K p110α, LXRα, FAS, SCD1, and LPL were found to be significantly higher, whereas PPARα and PPARγ were lower in GDM women compared with CPW. The placental TG content and cord plasma FFA were increased in GDM women compared with CPW. The placental TG content positively correlated with Ponderal index of GDM new-borns. Conclusion Differential expressions of placental proteins related to lipid metabolism in GDM might have led to placental TG accumulation. This might have contributed to the fetal overgrowth in GDM.

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Identification of a second human acetyl-CoA carboxylase gene

Biochemical Journal ◽

10.1042/bj3160915 ◽

1996 ◽

Vol 316 (3) ◽

pp. 915-922 ◽

Cited By ~ 53

Author(s):

Jane WIDMER ◽

Katherine S. FASSIHI ◽

Susannah C. SCHLICHTER ◽

Kate S. WHEELER ◽

Barbara E. CRUTE ◽

...

Keyword(s):

Fatty Acid ◽

Fatty Acid Biosynthesis ◽

Cultured Cells ◽

Regulatory Control ◽

Chromosome 17 ◽

Acid Oxidation ◽

Acetyl Coa Carboxylase ◽

Acetyl Coa ◽

Specific Expression ◽

Mrna Tissue Distribution

Acetyl-CoA carboxylase (ACC), an important enzyme in fatty acid biosynthesis and a regulator of fatty acid oxidation, is present in at least two isoenzymic forms in rat and human tissues. Previous work has established the existence of a 265000 Da enzyme in both the rat and human (RACC265; HACC265) and a higher-molecular-mass species (275000–280000 Da) in the same species (RACC280; HACC275). An HACC265 gene has previously been localized to chromosome 17. In the present study, we report cloning of a partial-length human cDNA sequence which appears to correspond to HACC275 and its rat homologue, RACC280, as judged by mRNA tissue distribution and cell-specific regulation of mRNA/protein expression. The gene encoding this isoenzymic form of ACC has been localized to the long arm of human chromosome 12. Thus, ACC is represented in a multigene family in both rodents and humans. The newly discovered human gene and its rat homologue appear to be under different regulatory control to the HACC265 gene, as judged by tissue-specific expression in vivo and by independent modulation in cultured cells in vitro.

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High glucose levels reduce fatty acid oxidation and increase triglyceride accumulation in human placenta

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00032.2013 ◽

2013 ◽

Vol 305 (2) ◽

pp. E205-E212 ◽

Cited By ~ 45

Author(s):

Francisco Visiedo ◽

Fernando Bugatto ◽

Viviana Sánchez ◽

Irene Cózar-Castellano ◽

Jose L. Bartha ◽

...

Keyword(s):

Fatty Acid ◽

High Glucose ◽

De Novo ◽

Acid Synthesis ◽

Acid Oxidation ◽

Glucose Levels ◽

Triglyceride Accumulation ◽

Triglyceride Content ◽

Low Glucose ◽

Cpt I

Placentas of women with gestational diabetes mellitus (GDM) exhibit an altered lipid metabolism. The mechanism by which GDM is linked to alterations in placental lipid metabolism remains obscure. We hypothesized that high glucose levels reduce mitochondrial fatty acid oxidation (FAO) and increase triglyceride accumulation in human placenta. To test this hypothesis, we measured FAO, fatty acid esterification, de novo fatty acid synthesis, triglyceride levels, and carnitine palmitoyltransferase activities (CPT) in placental explants of women with GDM or no pregnancy complication. In women with GDM, FAO was reduced by ∼30% without change in mitochondrial content, and triglyceride content was threefold higher than in the control group. Likewise, in placental explants of women with no complications, high glucose levels reduced FAO by ∼20%, and esterification increased linearly with increasing fatty acid concentrations. However, de novo fatty acid synthesis remained unchanged between high and low glucose levels. In addition, high glucose levels increased triglyceride content approximately twofold compared with low glucose levels. Furthermore, etomoxir-mediated inhibition of FAO enhanced esterification capacity by ∼40% and elevated triglyceride content 1.5-fold in placental explants of women, with no complications. Finally, high glucose levels reduced CPT I activity by ∼70% and phosphorylation levels of acetyl-CoA carboxylase by ∼25% in placental explants of women, with no complications. We reveal an unrecognized regulatory mechanism on placental fatty acid metabolism by which high glucose levels reduce mitochondrial FAO through inhibition of CPT I, shifting flux of fatty acids away from oxidation toward the esterification pathway, leading to accumulation of placental triglycerides.

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