Sirtuin 1 is involved in oleic acid-induced calf hepatocyte steatosis via alterations in lipid metabolism-related proteins

2021 ◽  
Vol 99 (10) ◽  
Author(s):  
Hongyan Ding ◽  
Yu Li ◽  
Leihong Liu ◽  
Ning Hao ◽  
Suping Zou ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Mrna Abundance ◽  
Sirtuin 1 ◽  
Peroxisome Proliferator ◽  
Acetyl Coa Carboxylase ◽  
Peroxisome Proliferator Activated Receptor ◽  
Lower Protein ◽  
Tag Accumulation

Abstract Sirtuin 1 (SIRT1), an NAD-dependent protein deacetylase, plays a central role in the control of lipid metabolism in nonruminants. However, the role of SIRT1 in hepatic lipid metabolism in dairy cows with fatty liver is not well known. Thus, we used isolated primary bovine hepatocytes to determine the role of SIRT1 in protecting cells against oleic acid (OA)-induced steatosis. Recombinant adenoviruses to overexpress (AD-GFP-SIRT1-E) or knockdown (AD-GFP-SIRT1-N) SIRT1 were used for transduction of hepatocytes. Calf hepatocytes isolated from five female calves (1 d old, 30 to 40 kg) were used to determine both time required and the lowest dose of OA that could induce triacylglycerol (TAG) accumulation. Analyses indicated that 0.25 mM OA for 24 h was suitable to induce TAG accumulation. In addition, OA not only led to an increase in TAG, but also upregulated mRNA and protein abundance of sterol regulatory element-binding transcription factor 1 (SREBF1) and downregulated SIRT1 and peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PPARGC1A). Thus, these in vitro conditions were deemed optimal for subsequent experiments. Calf hepatocytes were cultured and incubated with OA (0.25 mM) for 24 h, followed by adenoviral AD-GFP-SIRT1-E or AD-GFP-SIRT1-N transduction for 48 h. Overexpression of SIRT1 led to greater protein and mRNA abundance of SIRT1 along with fatty acid oxidation-related genes including PPARGC1A, peroxisome proliferator-activated receptor alpha (PPARA), retinoid X receptor α (RXRA), and ratio of phospho-acetyl-CoA carboxylase alpha (p-ACACA)/total acetyl-CoA carboxylase alpha (ACACA). In contrast, it resulted in lower protein and mRNA abundance of genes related to lipid synthesis including SREBF1, fatty acid synthase (FASN), apolipoprotein E (APOE), and low-density lipoprotein receptor (LDLR). The concentration of TAG decreased due to SIRT1 overexpression. In contrast, silencing SIRT1 led to lower protein and mRNA abundance of SIRT1, PPARGC1A, PPARA, RXRA, and greater protein and mRNA abundance of SREBF1, FASN, APOE, and LDLR. Further, those responses were accompanied by greater content of cellular TAG and total cholesterol (TC). Overall, data from these in vitro studies indicated that SIRT1 is involved in the regulation of lipid metabolism in calf hepatocytes subjected to an increase in the supply of OA. Thus, it is possible that alterations in SIRT1 abundance and activity in vivo contribute to development of fatty liver in dairy cows.

scholarly journals The Novel Role of PGC1α in Bone Metabolism

2021 ◽  
Vol 22 (9) ◽  
pp. 4670
Author(s):  
Cinzia Buccoliero ◽  
Manuela Dicarlo ◽  
Patrizia Pignataro ◽  
Francesco Gaccione ◽  
Silvia Colucci ◽  
...  
Keyword(s):  
Bone Metabolism ◽  
Osteoblastic Differentiation ◽  
In Vivo Studies ◽  
Peroxisome Proliferator ◽  
Sirtuin 3 ◽  
Peroxisome Proliferator Activated Receptor ◽  
Increased Risk

Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) is a protein that promotes transcription of numerous genes, particularly those responsible for the regulation of mitochondrial biogenesis. Evidence for a key role of PGC1α in bone metabolism is very recent. In vivo studies showed that PGC1α deletion negatively affects cortical thickness, trabecular organization and resistance to flexion, resulting in increased risk of fracture. Furthermore, in a mouse model of bone disease, PGC1α activation stimulates osteoblastic gene expression and inhibits atrogene transcription. PGC1α overexpression positively affects the activity of Sirtuin 3, a mitochondrial nicotinammide adenina dinucleotide (NAD)-dependent deacetylase, on osteoblastic differentiation. In vitro, PGC1α overexpression prevents the reduction of mitochondrial density, membrane potential and alkaline phosphatase activity caused by Sirtuin 3 knockdown in osteoblasts. Moreover, PGC1α influences the commitment of skeletal stem cells towards an osteogenic lineage, while negatively affects marrow adipose tissue accumulation. In this review, we will focus on recent findings about PGC1α action on bone metabolism, in vivo and in vitro, and in pathologies that cause bone loss, such as osteoporosis and type 2 diabetes.

scholarly journals Role of Hyaluronan in Human Adipogenesis: Evidence from in-Vitro and in-Vivo Studies

2019 ◽  
Vol 20 (11) ◽  
pp. 2675 ◽  
Author(s):  
Nicholas Wilson ◽  
Robert Steadman ◽  
Ilaria Muller ◽  
Mohd Draman ◽  
D. Aled Rees ◽  
...  
Keyword(s):  
Stem Cell Differentiation ◽  
In Vivo Studies ◽  
Peroxisome Proliferator ◽  
Synthesis Inhibitor ◽  
Peroxisome Proliferator Activated Receptor ◽  
Inhibitory Role ◽  
The Impact

Hyaluronan (HA), an extra-cellular matrix glycosaminoglycan, may play a role in mesenchymal stem cell differentiation to fat but results using murine models and cell lines are conflicting. Our previous data, illustrating decreased HA production during human adipogenesis, suggested an inhibitory role. We have investigated the role of HA in adipogenesis and fat accumulation using human primary subcutaneous preadipocyte/fibroblasts (PFs, n = 12) and subjects of varying body mass index (BMI). The impact of HA on peroxisome proliferator-activated receptor gamma (PPARγ) expression was analysed following siRNA knockdown or HA synthase (HAS)1 and HAS2 overexpression. PFs were cultured in complete or adipogenic medium (ADM) with/without 4-methylumbelliferone (4-MU = HA synthesis inhibitor). Adipogenesis was evaluated using oil red O (ORO), counting adipogenic foci, and measurement of a terminal differentiation marker. Modulating HA production by HAS2 knockdown or overexpression increased (16%, p < 0.04) or decreased (30%, p = 0.01) PPARγ transcripts respectively. The inhibition of HA by 4-MU significantly enhanced ADM-induced adipogenesis with 1.52 ± 0.18- (ORO), 4.09 ± 0.63- (foci) and 2.6 ± 0.21-(marker)-fold increases compared with the controls, also increased PPARγ protein expression (40%, (p < 0.04)). In human subjects, circulating HA correlated negatively with BMI and triglycerides (r = −0.396 (p = 0.002), r = −0.269 (p = 0.038), respectively), confirming an inhibitory role of HA in human adipogenesis. Thus, enhancing HA action may provide a therapeutic target in obesity.

scholarly journals IL-15 Is Required for Postexercise Induction of the Pro-Oxidative Mediators PPARδ and SIRT1 in Male Mice

Endocrinology ◽  
2014 ◽  
Vol 155 (1) ◽  
pp. 143-155 ◽  
Author(s):  
LeBris S. Quinn ◽  
Barbara G. Anderson ◽  
Jennifer D. Conner ◽  
Tami Wolden-Hanson ◽  
Taylor J. Marcell
Keyword(s):  
Physical Exercise ◽  
Gastrocnemius Muscle ◽  
Sirtuin 1 ◽  
Treadmill Running ◽  
Separate Experiment ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Protein Levels ◽  
Deficient Mice

Physical exercise induces transient upregulation of the pro-oxidative mediators peroxisome proliferator-activated receptor-δ (PPARδ), silent information regulator of transcription (sirtuin)-1 (SIRT1), PPARγ coactivator 1α (PGC-1α), and PGC-1β in skeletal muscle. To determine the role of the cytokine IL-15 in acute postexercise induction of these molecules, expression of these factors after a bout of exhaustive treadmill running was examined in the gastrocnemius muscle of untrained control and IL-15–knockout (KO) mice. Circulating IL-15 levels increased transiently in control mice after exercise. Control mice, but not IL-15–KO mice, upregulated muscle PPARδ and SIRT1 protein after exercise, accompanied by a complex pattern of mRNA expression for these factors. However, in exhaustive exercise, control mice ran significantly longer than IL-15–KO mice. Therefore, in a second experiment, mice were limited to a 20-minute run, after which a similar pattern of induction of muscle PPARδ and SIRT1 protein by control mice only was observed. In a separate experiment, IL-15–KO mice injected systemically with recombinant IL-15 upregulated muscle PPARδ and SIRT1 mRNA within 30 minutes and also exhibited increased muscle PPARδ protein levels by 3 hours. After exercise, both control and IL-15–KO mice downregulated IL-15 receptor-α (IL-15Rα) mRNA, whereas IL-15Rα–deficient mice exhibited constitutively elevated circulating IL-15 levels. These observations indicate IL-15 release after exercise is necessary for induction of PPARδ and SIRT1 at the protein level in muscle tissue and suggest that exercise releases IL-15 normally sequestered by the IL-15Rα in the resting state. These findings could be used to develop an IL-15–based strategy to induce many of the metabolic benefits of physical exercise.

scholarly journals Angiogenic Deficiency and Adipose Tissue Dysfunction Are Associated with Macrophage Malfunction in SIRT1−/− Mice

Endocrinology ◽  
2012 ◽  
Vol 153 (4) ◽  
pp. 1706-1716 ◽  
Author(s):  
Fen Xu ◽  
David Burk ◽  
Zhanguo Gao ◽  
Jun Yin ◽  
Xia Zhang ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Adipocyte Differentiation ◽  
Nuclear Factor Κb ◽  
The Body ◽  
Sirtuin 1 ◽  
Vascular Density ◽  
Peroxisome Proliferator ◽  
Wild Type ◽  
Peroxisome Proliferator Activated Receptor

The histone deacetylase sirtuin 1 (SIRT1) inhibits adipocyte differentiation and suppresses inflammation by targeting the transcription factors peroxisome proliferator-activated receptor γ and nuclear factor κB. Although this suggests that adiposity and inflammation should be enhanced when SIRT1 activity is inactivated in the body, this hypothesis has not been tested in SIRT1 null (SIRT1−/−) mice. In this study, we addressed this issue by investigating the adipose tissue in SIRT1−/− mice. Compared with their wild-type littermates, SIRT1 null mice exhibited a significant reduction in body weight. In adipose tissue, the average size of adipocytes was smaller, the content of extracellular matrix was lower, adiponectin and leptin were expressed at 60% of normal level, and adipocyte differentiation was reduced. All of these changes were observed with a 50% reduction in capillary density that was determined using a three-dimensional imaging technique. Except for vascular endothelial growth factor, the expression of several angiogenic factors (Pdgf, Hgf, endothelin, apelin, and Tgf-β) was reduced by about 50%. Macrophage infiltration and inflammatory cytokine expression were 70% less in the adipose tissue of null mice and macrophage differentiation was significantly inhibited in SIRT1−/− mouse embryonic fibroblasts in vitro. In wild-type mice, macrophage deletion led to a reduction in vascular density. These data suggest that SIRT1 controls adipose tissue function through regulation of angiogenesis, whose deficiency is associated with macrophage malfunction in SIRT1−/− mice. The study supports the concept that inflammation regulates angiogenesis in the adipose tissue.

scholarly journals Natural and Synthetic PPARγ Ligands in Tumor Microenvironment: A New Potential Strategy against Breast Cancer

2020 ◽  
Vol 21 (24) ◽  
pp. 9721
Author(s):  
Giuseppina Augimeri ◽  
Luca Gelsomino ◽  
Pierluigi Plastina ◽  
Cinzia Giordano ◽  
Ines Barone ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Microenvironment ◽  
Complex Disease ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Extracellular Matrix Components ◽  
Potential Strategy

Multiple lines of evidence indicate that activation of the peroxisome proliferator-activated receptor γ (PPARγ) by natural or synthetic ligands exerts tumor suppressive effects in different types of cancer, including breast carcinoma. Over the past decades a new picture of breast cancer as a complex disease consisting of neoplastic epithelial cells and surrounding stroma named the tumor microenvironment (TME) has emerged. Indeed, TME is now recognized as a pivotal element for breast cancer development and progression. Novel strategies targeting both epithelial and stromal components are under development or undergoing clinical trials. In this context, the aim of the present review is to summarize PPARγ activity in breast TME focusing on the role of this receptor on both epithelial/stromal cells and extracellular matrix components of the breast cancer microenvironment. The information provided from the in vitro and in vivo research indicates PPARγ ligands as potential agents with regards to the battle against breast cancer.

scholarly journals PPARs as Metabolic Regulators in the Liver: Lessons from Liver-Specific PPAR-Null Mice

2020 ◽  
Vol 21 (6) ◽  
pp. 2061 ◽  
Author(s):  
Yaping Wang ◽  
Takero Nakajima ◽  
Frank J. Gonzalez ◽  
Naoki Tanaka
Keyword(s):  
Fatty Acid ◽  
Lipid Metabolism ◽  
Liver Cancer ◽  
Energy Homeostasis ◽  
Whole Body ◽  
Lipid Homeostasis ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Metabolic Regulators

Peroxisome proliferator-activated receptor (PPAR) α, β/δ, and γ modulate lipid homeostasis. PPARα regulates lipid metabolism in the liver, the organ that largely controls whole-body nutrient/energy homeostasis, and its abnormalities may lead to hepatic steatosis, steatohepatitis, steatofibrosis, and liver cancer. PPARβ/δ promotes fatty acid β-oxidation largely in extrahepatic organs, and PPARγ stores triacylglycerol in adipocytes. Investigations using liver-specific PPAR-disrupted mice have revealed major but distinct contributions of the three PPARs in the liver. This review summarizes the findings of liver-specific PPAR-null mice and discusses the role of PPARs in the liver.

scholarly journals Low Expression of Sirtuin 1 in the Dairy Cows with Mild Fatty Liver Alters Hepatic Lipid Metabolism

Animals ◽  
2020 ◽  
Vol 10 (4) ◽  
pp. 560
Author(s):  
Yu Li ◽  
Suping Zou ◽  
Hongyan Ding ◽  
Ning Hao ◽  
Yingying Huang ◽  
...  
Keyword(s):  
Superoxide Dismutase ◽  
Fatty Acid ◽  
Lipid Metabolism ◽  
Fatty Liver ◽  
Dairy Cows ◽  
Milk Production ◽  
Sirtuin 1 ◽  
Peroxisome Proliferator ◽  
Protein Abundance ◽  
Peroxisome Proliferator Activated Receptor

Dairy cows usually experience negative energy balance coupled with an increased incidence of fatty liver during the periparturient period. The purpose of this study was to investigate the effect of hepatic steatosis on the expression of the sirtuin 1 (SIRT1), along with the target mRNA and protein expressions and activities related to lipid metabolism in liver tissue. Control cows (n = 6, parity 3.0 ± 2.0, milk production 28 ± 7 kg/d) and mild fatty liver cows (n = 6, parity 2.3 ± 1.5, milk production 20 ± 6 kg/d) were retrospectively selected based on liver triglycerides (TG) content (% wet liver). Compared with the control group, fatty liver cows had greater concentrations of cholesterol and TG along with the typically vacuolated appearance and greater lipid droplets in the liver. Furthermore, fatty liver cows had greater mRNA and protein abundance related to hepatic lipid synthesis proteins sterol regulatory element binding proteins (SREBP-1c), long-chain acyl-CoA synthetase (ACSL), acyl-CoA carbrolase (ACC) and fatty acid synthase (FAS) and lipid transport proteins Liver fatty acid binding protein (L-FABP), apolipoprotein E (ApoE), low density lipoprotein receptor (LDLR) and microsomal TG transfer protein (MTTP) (p < 0.05). However, they had lower mRNA and protein abundance associated with fatty acid β-oxidation proteins SIRT1, peroxisome proliferator-activated receptor co-activator-1 (PGC-1α), peroxisome proliferator–activated receptor-α (PPARα), retinoid X receptor (RXRα), acyl-CoA 1 (ACO), carnitine palmitoyltransferase 1 (CPT1), carnitine palmitoyltransferase 2 (CPT2) and long- and medium-chain 3-hydroxyacyl-CoA dehydrogenases (LCAD) (p < 0.05). Additionally, mRNA abundance and enzyme activity of enzymes copper/zinc superoxide dismutase (Cu/Zn SOD), catalase (CAT), glutathione peroxidase (GSH-Px) and manganese superoxide dismutase (Mn SOD) decreased and mRNA and protein abundance of p45 nuclear factor-erythroid 2 (p45 NF-E2)-related factor 1 (Nrf1), mitochondrial transcription factor A (TFAM) decreased (p < 0.05). Lower enzyme activities of SIRT1, PGC-1α, Cu/Zn SOD, CAT, GSH-Px, SREBP-1c and Mn SOD (p < 0.05) and concentration of reactive oxygen species (ROS) were observed in dairy cows with fatty liver. These results demonstrate that decreased SIRT1 associated with hepatic steatosis promotes hepatic fatty acid synthesis and inhibits fatty acid β-oxidation. Hence, SIRT1 may represent a novel therapeutic target for the treatment of the fatty liver disease in dairy cows.

scholarly journals The E3 ligase MARCH5 is a PPARγ target gene that regulates mitochondria and metabolism in adipocytes

2019 ◽  
Vol 316 (2) ◽  
pp. E293-E304 ◽  
Author(s):  
Simon T. Bond ◽  
Sarah C. Moody ◽  
Yingying Liu ◽  
Mete Civelek ◽  
Claudio J. Villanueva ◽  
...  
Keyword(s):  
Mitochondrial Function ◽  
Mitochondrial Dynamics ◽  
Mouse Strains ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Metabolic Genes ◽  
And Function

Mitochondrial dynamics refers to the constant remodeling of mitochondrial populations by multiple cellular pathways that help maintain mitochondrial health and function. Disruptions in mitochondrial dynamics often lead to mitochondrial dysfunction, which is frequently associated with disease in rodents and humans. Consistent with this, obesity is associated with reduced mitochondrial function in white adipose tissue, partly via alterations in mitochondrial dynamics. Several proteins, including the E3 ubiquitin ligase membrane-associated RING-CH-type finger 5 (MARCH5), are known to regulate mitochondrial dynamics; however, the role of these proteins in adipocytes has been poorly studied. Here, we show that MARCH5 is regulated by peroxisome proliferator-activated receptor-γ (PPARγ) during adipogenesis and is correlated with fat mass across a panel of genetically diverse mouse strains, in ob/ob mice, and in humans. Furthermore, manipulation of MARCH5 expression in vitro and in vivo alters mitochondrial function, affects cellular metabolism, and leads to differential regulation of several metabolic genes. Thus our data demonstrate an association between mitochondrial dynamics and metabolism that defines MARCH5 as a critical link between these interconnected pathways.

scholarly journals LRRK2 Regulates CPT1A to Promote β-Oxidation in HepG2 Cells

Molecules ◽  
2020 ◽  
Vol 25 (18) ◽  
pp. 4122 ◽  
Author(s):  
Chiao-Wei Lin ◽  
Yu-Ju Peng ◽  
Yuan-Yu Lin ◽  
Harry John Mersmann ◽  
Shih-Torng Ding
Keyword(s):  
Lipid Metabolism ◽  
Hepg2 Cells ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Alcoholic Fatty Liver ◽  
Cytokine Tumor Necrosis Factor ◽  
Factor Α ◽  
Amp Activated Protein Kinase ◽  
Necrosis Factor

Leucine-rich repeat kinase 2 (LRRK2) is involved in lipid metabolism; however, the role of LRRK2 in lipid metabolism to affect non-alcoholic fatty liver disease (NAFLD) is still unclear. In the mouse model of NAFLD induced by a high-fat diet, we observed that LRRK2 was decreased in livers. In HepG2 cells, exposure to palmitic acid (PA) down-regulated LRRK2. Overexpression and knockdown of LRRK2 in HepG2 cells were performed to further investigate the roles of LRRK2 in lipid metabolism. Our results showed that β-oxidation in HepG2 cells was promoted by LRRK2 overexpression, whereas LRRK2 knockdown inhibited β-oxidation. The critical enzyme of β-oxidation, carnitine palmitoyltransferase 1A (CPT1A), was positively regulated by LRRK2. Our data suggested that the regulation of CPT1A by LRRK2 may be via the activation of AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor α (PPARα). The overexpression of LRRK2 reduced the concentration of a pro-inflammatory cytokine, tumor necrosis factor α (TNFα), induced by PA. The increase in β-oxidation may promote lipid catabolism to suppress inflammation induced by PA. These results indicated that LRRK2 participated in the regulation of β-oxidation and suggested that the decreased LRRK2 may promote inflammation by suppressing β-oxidation in the liver.

scholarly journals Interferon-Stimulated Gene ISG12b1 Inhibits Adipogenic Differentiation and Mitochondrial Biogenesis in 3T3-L1 Cells

Endocrinology ◽  
2008 ◽  
Vol 150 (3) ◽  
pp. 1217-1224 ◽  
Author(s):  
Bing Li ◽  
Jonghyun Shin ◽  
Kichoon Lee
Keyword(s):  
Mitochondrial Biogenesis ◽  
Adipogenic Differentiation ◽  
Peroxisome Proliferator ◽  
Mitochondrial Transcription ◽  
Peroxisome Proliferator Activated Receptor ◽  
And Function ◽  
Adipocyte Development

Microarray analysis was performed to find a new group of genes or pathways that might be important in adipocyte development and metabolism. Among them, a mouse interferon-stimulated gene 12b1 (ISG12b1) is expressed at a 400-fold higher level in adipocytes compared with stromal-vascular cells. It is predominantly expressed in adipose tissue among other tissues we tested. Developmentally, ISG12b1 mRNA expression was initially inhibited followed by a dramatic induction during both in vivo and in vitro adipogenic differentiation. Adenovirus-mediated overexpression of ISG12b1 inhibited adipogenic differentiation in 3T3-L1 cells as shown by decreased lipid staining with Oil-Red-O and reduction in adipogenic marker proteins including peroxisome proliferator-activated receptor-γ (PPARγ), and CCAAT/enhancer-binding protein-α (C/EBPα). Our bioinformatics analysis for the predicted localization of ISG12b1 protein suggested the mitochondrial localization, which was confirmed by the colocalization of hemagglutinin-tagged ISG12b1 protein with mitochondrial marker MitoTracker. In addition, ISG12b1 protein was exclusively detected in protein extract from the fractionated mitochondria by Western blot analysis. Furthermore, overexpression of ISG12b1 in adipocytes reduced mitochondrial DNA content and gene expression of mitochondrial transcription factor A (mtTFA), nuclear respiratory factor 1 (NRF1), and cytochrome oxidase II, suggesting an inhibitory role of ISG12b1 in mitochondrial biogenesis and function. Activation of mitochondrial biogenesis and function by treatment with PPARγ and PPARα agonists in 3T3-L1 cells and cold exposure in mice induced mitochondrial transcription factors and reduced ISG12 expression. These data demonstrated that mitochondrial-localized ISG12b1 protein inhibits adipocyte differentiation and mitochondrial biogenesis and function, implying the important role of mitochondrial function in adipocyte development and associated diseases. ISG12b1 is predominantly expressed in adipocytes and dramatically induced at the terminal stage of adipogenesis. Functionally, mitochondria-localized ISG12b1 inhibits adipogenic differentiation and mitochondria biogenesis.

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