scholarly journals Dietary Polyphenols Protect Against Oleic Acid-Induced Steatosis in an in Vitro Model of NAFLD by Modulating Lipid Metabolism and Improving Mitochondrial Function

Nutrients ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 541 ◽  
Author(s):  
Hossein Rafiei ◽  
Kosar Omidian ◽  
Brian Bandy
Keyword(s):  
Oleic Acid ◽  
Lipid Metabolism ◽  
Cell Morphology ◽  
Mitochondrial Function ◽  
Molecular Mechanisms ◽  
Relative Effectiveness ◽  
Acid Oxidation ◽  
Alcoholic Fatty Liver ◽  
Dietary Polyphenols

In this study, we aimed to determine the relative effectiveness of common dietary polyphenols or the isoquinoline alkaloid berberine in protecting against molecular mechanisms underlying non-alcoholic fatty liver disease (NAFLD) involving changes to cellular lipid metabolism and bioenergetics. In a model of steatosis using HepG2 hepatocytes, exposure of the cells to 1.5 mM oleic acid (OA) for 24 h caused steatosis and distorted cell morphology, induced the expression of mRNA for enzymes that are involved in lipogenesis and fatty acid oxidation (FAS and CPT1A), and impaired indices of aerobic energy metabolism (PPARγ mRNA expression, mitochondrial membrane potential (MMP), and galactose-supported ATP production). Co-treatment with 10 µM of selected polyphenols all strongly protected against the steatosis and changes in cell morphology. All polyphenols, except cyanidin, inhibited the effects on FAS and PPARγ and further increased CPT1A1 expression, suggesting a shift toward increased β-oxidation. Resveratrol, quercetin, catechin, and cyanidin, however not kuromanin or berberine, ameliorated the decreases in MMP and galactose-derived ATP. Berberine was unique in worsening the decrease in galactose-derived ATP. In further investigations of the mechanisms involved, resveratrol, catechin, and berberine increased SIRT1 enzyme activity and p-AMPKαThr172 protein, which are involved in mitochondrial biogenesis. In conclusion, selected polyphenols all protected against steatosis with similar effectiveness, however through different mechanisms that increased aerobic lipid metabolism and mitochondrial function.

scholarly journals Copper restoration by liver Ceruloplasmin ablation ameliorates NAFLD via SCO1-AMPK-LKB1 complex

2021 ◽  
Author(s):  
Junli Liu ◽  
Liping Xie ◽  
Yanmei Yuan ◽  
Simiao Xu ◽  
Sijia Lu ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Molecular Mechanisms ◽  
Acid Oxidation ◽  
Alcoholic Fatty Liver ◽  
Ampk Signaling ◽  
Hepatic Copper ◽  
Copper Loss ◽  
Lipid Catabolism ◽  
Wide Range ◽  
Essential Nutrient

Abstract Copper is an essential nutrient and a co-factor of numerous enzymes governing a wide range of intracellular processes. Copper deficiency has emerged to be associated with various lipid metabolism diseases, including non-alcoholic fatty liver disease (NAFLD). However, the molecular mechanisms of how copper regulates lipid metabolism and is sensed remain elusive. Here, we reveal that copper elevation caused by hepatic ceruloplasmin (CP) ablation enhances lipid catabolism by promoting the assembly of copper-load SCO1/AMPK complex. We report that overnutrition-mediated CP elevation results in hepatic copper loss, and that liver-specific CP ablation counteracts this reduction in copper levels and ameliorates NAFLD in mice. Mechanistically, SCO1 constitutively interacts with LKB1 even in the absence of copper, and copper-loaded SCO1 directly tethers LKB1 to AMPK, thereby activating AMPK and consequently promoting mitochondrial biogenesis and fatty acid oxidation in hepatocytes. Therefore, this study reveals an unexpected role for AMPK to sense copper alteration via SCO1 and uncovers a previously unidentified mechanism by which copper, as a signaling molecule, improves hepatic lipid catabolism, and indicates that targeting copper-AMPK signaling pathway ameliorates NAFLD development by modulating AMPK activity.

scholarly journals FAM92A1 is a BAR domain protein required for mitochondrial ultrastructure and function

2018 ◽  
Vol 218 (1) ◽  
pp. 97-111 ◽  
Author(s):  
Liang Wang ◽  
Ziyi Yan ◽  
Helena Vihinen ◽  
Ove Eriksson ◽  
Weihuan Wang ◽  
...  
Keyword(s):  
Mitochondrial Function ◽  
Molecular Mechanisms ◽  
Membrane Curvature ◽  
Mitochondrial Morphology ◽  
Membrane Remodeling ◽  
Mitochondrial Ultrastructure ◽  
Bar Domain ◽  
Bar Domain Proteins ◽  
Domain Protein

Mitochondrial function is closely linked to its dynamic membrane ultrastructure. The mitochondrial inner membrane (MIM) can form extensive membrane invaginations known as cristae, which contain the respiratory chain and ATP synthase for oxidative phosphorylation. The molecular mechanisms regulating mitochondrial ultrastructure remain poorly understood. The Bin-Amphiphysin-Rvs (BAR) domain proteins are central regulators of diverse cellular processes related to membrane remodeling and dynamics. Whether BAR domain proteins are involved in sculpting membranes in specific submitochondrial compartments is largely unknown. In this study, we report FAM92A1 as a novel BAR domain protein localizes to the matrix side of the MIM. Loss of FAM92A1 caused a severe disruption to mitochondrial morphology and ultrastructure, impairing organelle bioenergetics. Furthermore, FAM92A1 displayed a membrane-remodeling activity in vitro, inducing a high degree of membrane curvature. Collectively, our findings uncover a role for a BAR domain protein as a critical organizer of the mitochondrial ultrastructure that is indispensable for mitochondrial function.

Plant polyphenols: free radical scavengers or chain-breaking antioxidants?

1995 ◽  
Vol 61 ◽  
pp. 103-116 ◽  
Author(s):  
Catherine Rice-Evans
Keyword(s):  
Biological Effects ◽  
Relative Effectiveness ◽  
Antioxidant Properties ◽  
Peroxyl Radicals ◽  
Free Radical Scavengers ◽  
Dietary Polyphenols ◽  
Chain Breaking ◽  
Lipid Peroxyl Radicals

There is increasing interest in the biological effects of tea- and wine-derived polyphenols and many studies in vitro and in vivo are demonstrating their antioxidant properties. Tea is a major source of dietary polyphenols and an even richer source of the flavanols, the catechins and catechin/gallate esters. Although there are limited studies on the bioavailability of the polyphenols, the absorption of flavanols in humans has been shown. The studies described in this chapter discuss the relative antioxidant potentials of the polyphenolic flavonoids in vitro against radicals generated in the aqueous phase in comparison with their relative effectiveness as antioxidants against propagating lipid peroxyl radicals, and how their activity influences that of α-tocopherol in low-density lipoproteins exposed to oxidative stress.

scholarly journals Phytochemicals from the Cocoa Shell Modulate Mitochondrial Function, Lipid and Glucose Metabolism in Hepatocytes via Activation of FGF21/ERK, AKT, and mTOR Pathways

Antioxidants ◽  
2022 ◽  
Vol 11 (1) ◽  
pp. 136
Author(s):  
Miguel Rebollo-Hernanz ◽  
Yolanda Aguilera ◽  
Maria A. Martin-Cabrejas ◽  
Elvira Gonzalez de Gonzalez de Mejia
Keyword(s):  
Oxidative Stress ◽  
Mitochondrial Function ◽  
Phosphoenolpyruvate Carboxykinase ◽  
Fatty Acid Synthase ◽  
Cell Model ◽  
Fibroblast Growth Factor 21 ◽  
Alcoholic Fatty Liver ◽  
Atp Production ◽  
Cocoa Shell

The cocoa shell is a by-product that may be revalorized as a source of bioactive compounds to prevent chronic cardiometabolic diseases. This study aimed to investigate the phytochemicals from the cocoa shell as targeted compounds for activating fibroblast growth factor 21 (FGF21) signaling and regulating non-alcoholic fatty liver disease (NAFLD)-related biomarkers linked to oxidative stress, mitochondrial function, and metabolism in hepatocytes. HepG2 cells treated with palmitic acid (PA, 500 µmol L−1) were used in an NAFLD cell model. Phytochemicals from the cocoa shell (50 µmol L−1) and an aqueous extract (CAE, 100 µg mL−1) enhanced ERK1/2 phosphorylation (1.7- to 3.3-fold) and FGF21 release (1.4- to 3.4-fold) via PPARα activation. Oxidative stress markers were reduced though Nrf-2 regulation. Mitochondrial function (mitochondrial respiration and ATP production) was protected by the PGC-1α pathway modulation. Cocoa shell phytochemicals reduced lipid accumulation (53–115%) and fatty acid synthase activity (59–93%) and prompted CPT-1 activity. Glucose uptake and glucokinase activity were enhanced, whereas glucose production and phosphoenolpyruvate carboxykinase activity were diminished. The increase in the phosphorylation of the insulin receptor, AKT, AMPKα, mTOR, and ERK1/2 conduced to the regulation of hepatic mitochondrial function and energy metabolism. For the first time, the cocoa shell phytochemicals are proved to modulate FGF21 signaling. Results demonstrate the in vitro preventive effect of the phytochemicals from the cocoa shell on NAFLD.

scholarly journals Intraperitoneal Triamcinolone Reduces Postoperative Adhesions, Possibly through Alteration of Mitochondrial Function

2022 ◽  
Vol 11 (2) ◽  
pp. 301
Author(s):  
Neeraja Purandare ◽  
Katherine J. Kramer ◽  
Paige Minchella ◽  
Sarah Ottum ◽  
Christopher Walker ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Mitochondrial Function ◽  
Molecular Mechanisms ◽  
Human Fibroblasts ◽  
Reactive Oxygen ◽  
Retrospective Chart Review ◽  
Oxygen Species ◽  
Abdominal Myomectomy ◽  
Hypoxic Conditions

Adhesions frequently occur postoperatively, causing morbidity. In this noninterventional observational cohort study, we enrolled patients who presented for repeat abdominal surgery, after a history of previous abdominal myomectomy, from March 1998 to June 20210 at St. Vincent’s Catholic Medical Centers. The primary outcome of this pilot study was to compare adhesion rates, extent, and severity in patients who were treated with intraperitoneal triamcinolone acetonide during the initial abdominal myomectomy (n = 31) with those who did not receive any antiadhesion interventions (n = 21), as documented on retrospective chart review. Adhesions were blindly scored using a standard scoring system. About 32% of patients were found to have adhesions in the triamcinolone group compared to 71% in the untreated group (p < 0.01). Compared to controls, adhesions were significantly less in number (0.71 vs. 2.09, p < 0.005), severity (0.54 vs. 1.38, p < 0.004), and extent (0.45 vs. 1.28, p < 0.003). To understand the molecular mechanisms, human fibroblasts were incubated in hypoxic conditions and treated with triamcinolone or vehicle. In vitro studies showed that triamcinolone directly prevents the surge of reactive oxygen species triggered by 2% hypoxia and prevents the increase in TGF-β1 that leads to the irreversible conversion of fibroblasts to an adhesion phenotype. Triamcinolone prevents the increase in reactive oxygen species through alterations in mitochondrial function that are HIF-1α-independent. Controlling mitochondrial function may thus allow for adhesion-free surgery and reduced postoperative complications.

scholarly journals Letrozole Accelerates Metabolic Remodeling through Activation of Glycolysis in Cardiomyocytes: A Role beyond Hormone Regulation

2022 ◽  
Vol 23 (1) ◽  
pp. 547
Author(s):  
Jun H. Heo ◽  
Sang R. Lee ◽  
Seong Lae Jo ◽  
Hyun Yang ◽  
Hye Won Lee ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Lipid Metabolism ◽  
Cancer Patients ◽  
Cardiovascular Effects ◽  
Female Rats ◽  
Acid Oxidation ◽  
Hormone Regulation ◽  
Breast Cancer Patients ◽  
Metabolic Remodeling

Estrogen receptor-positive (ER+) breast cancer patients are recommended hormone therapy as a primary adjuvant treatment after surgery. Aromatase inhibitors (AIs) are widely administered to ER+ breast cancer patients as estrogen blockers; however, their safety remains controversial. The use of letrozole, an AI, has been reported to cause adverse cardiovascular effects. We aimed to elucidate the effects of letrozole on the cardiovascular system. Female rats exposed to letrozole for four weeks showed metabolic changes, i.e., decreased fatty acid oxidation, increased glycolysis, and hypertrophy in the left ventricle. Although lipid oxidation yields more ATP than carbohydrate metabolism, the latter predominates in the heart under pathological conditions. Reduced lipid metabolism is attributed to reduced β-oxidation due to low circulating estrogen levels. In letrozole-treated rats, glycolysis levels were found to be increased in the heart. Furthermore, the levels of glycolytic enzymes were increased (in a high glucose medium) and the glycolytic rate was increased in vitro (H9c2 cells); the same was not true in the case of estrogen treatment. Reduced lipid metabolism and increased glycolysis can lower energy supply to the heart, resulting in predisposition to heart failure. These data suggest that a letrozole-induced cardiac metabolic remodeling, i.e., a shift from β-oxidation to glycolysis, may induce cardiac structural remodeling.

Abstract 76: MicroRNA-144 Regulates Hepatic ABCA1 and Plasma HDL Following Activation of the Nuclear Receptor FXR

2013 ◽  
Vol 33 (suppl_1) ◽  
Author(s):  
Thomas Vallim ◽  
Elizabeth Tarling ◽  
Tammy Kim ◽  
Mete Civelek ◽  
Angel Baldan ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Nuclear Receptor ◽  
Molecular Mechanisms ◽  
Lipoprotein Metabolism ◽  
Density Lipoprotein ◽  
Hdl Cholesterol ◽  
Farnesoid X Receptor ◽  
Abca1 Protein

Rationale The bile acid receptor Farnesoid-X-Receptor (FXR) regulates many aspects of lipid metabolism by various complex and not fully understood molecular mechanisms. We set out to investigate the molecular mechanisms for FXR-dependent regulation of lipid and lipoprotein metabolism. Objective To identify FXR-regulated microRNAs that were subsequently involved in regulating lipid metabolism. Methods and Results ATP binding cassette transporter A1 (ABCA1) is a major determinant of plasma High Density Lipoprotein (HDL)-cholesterol levels. Here we show that activation of the nuclear receptor FXR in vivo increases hepatic levels of miR-144, which in turn lower hepatic ABCA1 and plasma HDL levels. We identified two complementary sequences to miR-144 in the 3’ untranslated region (UTR) of ABCA1 mRNA that are necessary for miR-144-dependent regulation. Overexpression of miR-144 in vitro decreased both cellular ABCA1 protein and cholesterol efflux to lipid-poor apolipoprotein A-I (ApoA-I) protein, whilst overexpression in vivo reduced hepatic ABCA1 protein and plasma HDL- cholesterol. Conversely, silencing miR-144 in mice increased hepatic ABCA1 protein and HDL- cholesterol. In addition, we utilized tissue-specific FXR deficient mice to show that induction of miR-144 and FXR-dependent hypolipidemia requires hepatic, but not intestinal FXR. Finally, we identified functional FXR response elements (FXREs) upstream of the miR-144 locus, consistent with direct FXR regulation. Conclusion In conclusion, we have identified a pathway involving FXR, miR-144 and ABCA1 that together regulate plasma HDL cholesterol. This pathway may be therapeutically targeted in the future in order to increase HDL levels.

scholarly journals Hydroxytyrosol Plays Antiatherosclerotic Effects through Regulating Lipid Metabolism via Inhibiting the p38 Signal Pathway

2020 ◽  
Vol 2020 ◽  
pp. 1-12
Author(s):  
Xinxin Zhang ◽  
Yating Qin ◽  
Xiaoning Wan ◽  
Hao Liu ◽  
Chao Iv ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Molecular Mechanisms ◽  
Cholesterol Metabolism ◽  
Fold Increase ◽  
Heart Tissue ◽  
Control Group ◽  
Atherosclerotic Lesions ◽  
Serum Crp

Purpose. Hydroxytyrosol (HT) processes multiaspect pharmacological properties such as antithrombosis and antidiabetes. The aim of this study was to explore the antistherosclerotic roles and relevant mechanisms of HT. Methods. Male apoE-/- mice were randomly divided into 2 groups: the control group and the HT group (10 mg/kg/day orally). After 16 weeks, blood tissue, heart tissue, and liver tissue were obtained to detect the atherosclerotic lesions, histological analysis, lipid parameters, and inflammation. And the underlying molecular mechanisms of HT were also studied in vivo and in vitro. Results. HT administration significantly reduced the extent of atherosclerotic lesions in the aorta of apoE-/- mice. We found that HT markedly lowered the levels of serum TG, TC, and LDL-C approximately by 17.4% (p=0.004), 15.2% (p=0.003), and 17.9% (p=0.009), respectively, as well as hepatic TG and TC by 15.0% (p<0.001) and 12.3% (p=0.003), respectively, while inducing a 26.9% (p=0.033) increase in serum HDL-C. Besides, HT improved hepatic steatosis and lipid deposition. Then, we discovered that HT could regulate the signal flow of AMPK/SREBP2 and increase the expression of ABCA1, apoAI, and SRBI. In addition, HT reduced the levels of serum CRP, TNF-α, IL-1β, and IL-6 approximately by 23.5% (p<0.001), 27.8% (p<0.001), 18.4% (p<0.001), and 19.1% (p<0.001), respectively, and induced a 1.4-fold increase in IL-10 level (p=0.014). Further, we found that HT might regulate cholesterol metabolism via decreasing phosphorylation of p38, followed by activation of AMPK and inactivation of NF-κB, which in turn triggered the blockade of SREBP2/PCSK9 and upregulation of LDLR, apoAI, and ABCA1, finally leading to a reduction of LDL-C and increase of HDL-C in the circulation. Conclusion. Our results provide the first evidence that HT displays antiatherosclerotic actions via mediating lipid metabolism-related pathways through regulating the activities of inflammatory signaling molecules.

scholarly journals Proanthocyanidins Ameliorated Deficits of Lipid Metabolism in Type 2 Diabetes Mellitus Via Inhibiting Adipogenesis and Improving Mitochondrial Function

2020 ◽  
Vol 21 (6) ◽  
pp. 2029
Author(s):  
Fangfang Tie ◽  
Jifei Wang ◽  
Yuexin Liang ◽  
Shujun Zhu ◽  
Zhenhua Wang ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Lipid Metabolism ◽  
Mitochondrial Function ◽  
Underlying Mechanism ◽  
Mitochondrial Dysfunctions ◽  
Mitochondrial Mass

Proanthocyanidins are the major active compounds extracted from Iris lactea Pall. var. Chinensis (Fisch.) Koidz (I. lactea). Proanthocyanidins exhibit a variety of pharmacological activities such as anti-oxidation, anti-inflammation, anti-tumor, and lowering blood lipids. However, the underlying mechanism of its regulating effect on lipid metabolism in diabetic conditions remains unclear. The present study investigated the effects of I. lactea-derived proanthocyanidins on lipid metabolism in mice of type 2 diabetes mellitus (T2DM). Results demonstrated a beneficial effect of total proanthocyanidins on dysregulated lipid metabolism and hepatic steatosis in high-fat-diet/streptozocin (STZ)-induced T2DM. To identify the mechanisms, six flavan-3-ols were isolated from proanthocyanidins of I. lacteal and their effects on adipogenesis and dexamethasone (Dex)-induced mitochondrial dysfunctions in 3T3-L1 adipocytes were determined. In vitro studies showed flavan-3-ols inhibited adipogenesis and restored mitochondrial function after Dex-induced insulin resistance, being suggested by increased mitochondrial membrane potential, intracellular ATP contents, mitochondrial mass and mitochondrial biogenesis, and reduced reactive oxygen species. Among the six flavan-3-ols, procyanidin B3 and procyanidin B1 exhibited the strongest effects. Our study suggests potential of proanthocyanidins as therapeutic target for diabetes.

scholarly journals A Mitochondrial Approach to Cardiovascular Risk and Disease

2019 ◽  
Vol 25 (29) ◽  
pp. 3175-3194 ◽  
Author(s):  
Caroline D. Veloso ◽  
Getachew D. Belew ◽  
Luciana L. Ferreira ◽  
Luís F. Grilo ◽  
John G. Jones ◽  
...  
Keyword(s):  
Cardiovascular Risk ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Function ◽  
Energy Demand ◽  
Kidney Diseases ◽  
Ischemia Reperfusion ◽  
Protective Effects ◽  
Alcoholic Fatty Liver ◽  
Cardiovascular Morbidity And Mortality

Background: Cardiovascular diseases (CVDs) are a leading risk factor for mortality worldwide and the number of CVDs victims is predicted to rise through 2030. While several external parameters (genetic, behavioral, environmental and physiological) contribute to cardiovascular morbidity and mortality; intrinsic metabolic and functional determinants such as insulin resistance, hyperglycemia, inflammation, high blood pressure and dyslipidemia are considered to be dominant factors. Methods: Pubmed searches were performed using different keywords related with mitochondria and cardiovascular disease and risk. In vitro, animal and human results were extracted from the hits obtained. Results: High cardiac energy demand is sustained by mitochondrial ATP production, and abnormal mitochondrial function has been associated with several lifestyle- and aging-related pathologies in the developed world such as diabetes, non-alcoholic fatty liver disease (NAFLD) and kidney diseases, that in turn can lead to cardiac injury. In order to delay cardiac mitochondrial dysfunction in the context of cardiovascular risk, regular physical activity has been shown to improve mitochondrial parameters and myocardial tolerance to ischemia-reperfusion (IR). Furthermore, pharmacological interventions can prevent the risk of CVDs. Therapeutic agents that can target mitochondria, decreasing ROS production and improve its function have been intensively researched. One example is the mitochondria-targeted antioxidant MitoQ10, which already showed beneficial effects in hypertensive rat models. Carvedilol or antidiabetic drugs also showed protective effects by preventing cardiac mitochondrial oxidative damage. Conclusion: This review highlights the role of mitochondrial dysfunction in CVDs, also show-casing several approaches that act by improving mitochondrial function in the heart, contributing to decrease some of the risk factors associated with CVDs.

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