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 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 Convergence of IPMK and LKB1-AMPK Signaling Pathways on Metformin Action

2014 ◽  
Vol 28 (7) ◽  
pp. 1186-1193 ◽  
Author(s):  
Sookhee Bang ◽  
Yong Chen ◽  
Rexford S. Ahima ◽  
Sangwon F. Kim
Keyword(s):  
Molecular Mechanisms ◽  
Metabolic Diseases ◽  
Dominant Negative ◽  
Acid Oxidation ◽  
Ampk Activation ◽  
Inositol Polyphosphate ◽  
Murine Embryonic Fibroblast ◽  
Ampk Signaling ◽  
Protein Protein Interaction ◽  
Glucose And Lipid Metabolism

Metformin is a biguanide drug that is widely prescribed for type 2 diabetes. Metformin suppresses hepatic gluconeogenesis and increases fatty acid oxidation. Although studies have suggested that metformin acts, at least in part, via activation of the liver kinase B1 (LKB1)/AMP-activated protein kinase (AMPK) pathway, the specific molecular mechanisms underlying metformin's regulation of glucose and lipid metabolism have not been well delineated. Recently, we have shown that inositol polyphosphate multikinase (IPMK) plays an important role in cellular energy metabolism and glucose-mediated AMPK regulation. Here we investigated the role of IPMK in metformin-induced AMPK activation. We observed that metformin-mediated activation of AMPK was impaired in the absence of IPMK. Overexpression of wild-type IPMK was sufficient to restore LKB1-AMPK activation by either metformin or AICAR in IPMK−/− murine embryonic fibroblast cells, suggesting that IPMK may act as an upstream regulator of LKB1-AMPK signaling in response to metformin. Moreover, this regulation was mediated by protein-protein interaction between IPMK and LKB1 as a dominant-negative peptide, which abrogates this interaction, attenuated metformin's ability to activate AMPK. Our data demonstrate that IPMK plays an important role in LKB1/AMPK signaling and may be targeted for treatment of metabolic diseases.

scholarly journals DSS-induced colitis is associated with adipose tissue dysfunction and disrupted hepatic lipid metabolism leading to hepatosteatosis and dyslipidemia in mice

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jeonghyeon Kwon ◽  
Chungho Lee ◽  
Sungbaek Heo ◽  
Bobae Kim ◽  
Chang-Kee Hyun
Keyword(s):  
Adipose Tissue ◽  
Energy Homeostasis ◽  
Molecular Mechanisms ◽  
Activity Index ◽  
Intestinal Barrier ◽  
Intestinal Barrier Function ◽  
Acid Oxidation ◽  
Barrier Dysfunction ◽  
Alcoholic Fatty Liver ◽  
Brown Adipose

AbstractConsidering high prevalence of non-alcoholic fatty liver diseases (NAFLD) in patients with inflammatory bowel disease (IBD), this study aimed to elucidate molecular mechanisms for how intestinal inflammatory conditions are causally linked to hepatic steatosis and dyslipidemia. Both younger and older mice treated with acute or chronic dextran sodium sulfate (DSS) developed colitis, which was evidenced by weight loss, colon length shortening, and elevated disease activity index and inflammation score. They also showed decreased expression of intestinal barrier function-related proteins and elevated plasma lipopolysaccharide level, indicating DSS-induced barrier dysfunction and thereby increased permeability. Interestingly, they displayed phenotypes of hepatic fat accumulation and abnormal blood lipid profiles. This DSS-induced colitis-associated lipid metabolic dysfunction was due to overall disruption of metabolic processes including fatty acid oxidation, lipogenesis, lipolysis, reverse cholesterol transport, bile acid synthesis, and white adipose tissue browning and brown adipose tissue thermogenesis, most of which are mediated by key regulators of energy homeostasis such as FGF21, adiponectin, and irisin, via SIRT1/PGC-1α- and LXRα-dependent pathways. Our study suggests a potential molecular mechanism underlying the comorbidity of NAFLD and IBD, which could provide a key to understanding how the two diseases are pathogenically linked and discovering critical therapeutic targets for their treatment.

scholarly journals Playing Jekyll and Hyde—The Dual Role of Lipids in Fatty Liver Disease

Cells ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 2244
Author(s):  
Martijn R. Molenaar ◽  
Louis C. Penning ◽  
J. Bernd Helms
Keyword(s):  
Lipid Metabolism ◽  
Liver Disease ◽  
Fatty Liver ◽  
Hepatic Fibrosis ◽  
Lipid Accumulation ◽  
Fatty Liver Disease ◽  
Molecular Mechanisms ◽  
Stellate Cells ◽  
Alcoholic Fatty Liver ◽  
Hepatic Lipid Accumulation

Lipids play Jekyll and Hyde in the liver. On the one hand, the lipid-laden status of hepatic stellate cells is a hallmark of healthy liver. On the other hand, the opposite is true for lipid-laden hepatocytes—they obstruct liver function. Neglected lipid accumulation in hepatocytes can progress into hepatic fibrosis, a condition induced by the activation of stellate cells. In their resting state, these cells store substantial quantities of fat-soluble vitamin A (retinyl esters) in large lipid droplets. During activation, these lipid organelles are gradually degraded. Hence, treatment of fatty liver disease is treading a tightrope—unsophisticated targeting of hepatic lipid accumulation might trigger problematic side effects on stellate cells. Therefore, it is of great importance to gain more insight into the highly dynamic lipid metabolism of hepatocytes and stellate cells in both quiescent and activated states. In this review, part of the special issue entitled “Cellular and Molecular Mechanisms underlying the Pathogenesis of Hepatic Fibrosis 2020”, we discuss current and highly versatile aspects of neutral lipid metabolism in the pathogenesis of non-alcoholic fatty liver disease (NAFLD).

scholarly journals Involvement of adiponectin-SIRT1-AMPK signaling in the protective action of rosiglitazone against alcoholic fatty liver in mice

2010 ◽  
Vol 298 (3) ◽  
pp. G364-G374 ◽  
Author(s):  
Zheng Shen ◽  
Xiaomei Liang ◽  
Christopher Q. Rogers ◽  
Drew Rideout ◽  
Min You
Keyword(s):  
Fatty Acid ◽  
Fatty Liver ◽  
Fatty Acid Oxidation ◽  
Protective Action ◽  
Sirtuin 1 ◽  
Acid Oxidation ◽  
Adiponectin Receptors ◽  
Alcoholic Fatty Liver ◽  
Ampk Signaling ◽  
Ppar Γ

The development of alcoholic fatty liver is associated with reduced adipocyte-derived adiponectin levels, decreased hepatic adiponectin receptors, and deranged hepatic adiponectin signaling in animals. Peroxisomal proliferator-activated receptor-γ (PPAR-γ) plays a key role in the regulation of adiponectin in adipose tissue. The aim of the present study was to test the ability of rosiglitazone, a known PPAR-γ agonist, to reverse the inhibitory effects of ethanol on adiponectin expression and its hepatic signaling, and to attenuate alcoholic liver steatosis in mice. Mice were fed modified Lieber-DeCarli ethanol-containing liquid diets for 4 wk or pair-fed control diets. Four groups of mice were given a dose of either 3 or 10 mg·kg body wt−1·day−1 of rosiglitazone with or without ethanol in their diets for the last 2 wk of the feeding study. Coadministration of rosiglitazone and ethanol increased the expression and circulating levels of adiponectin and enhanced the expression of hepatic adiponectin receptors (AdipoRs) in mice. These increases correlated closely with the activation of a hepatic sirtuin 1 (SIRT1)-AMP-activated kinase (AMPK) signaling system. In concordance with stimulated SIRT1-AMPK signaling, rosiglitazone administration enhanced expression of fatty acid oxidation enzymes, normalized lipin 1 expression, and blocked elevated expression of genes encoding lipogenic enzymes which, in turn, led to increased fatty acid oxidation, reduced lipogenesis, and alleviation of steatosis in the livers of ethanol-fed mice. Enhanced hepatic adiponectin-SIRT1-AMPK signaling contributes, at least in part, to the protective action of rosiglitazone against alcoholic fatty liver in mice.

scholarly journals Plant-Based Foods and Their Bioactive Compounds on Fatty Liver Disease: Effects, Mechanisms, and Clinical Application

2021 ◽  
Vol 2021 ◽  
pp. 1-23
Author(s):  
Hang-Yu Li ◽  
Ren-You Gan ◽  
Ao Shang ◽  
Qian-Qian Mao ◽  
Quan-Cai Sun ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Liver Disease ◽  
Fatty Liver ◽  
Clinical Application ◽  
Bioactive Compounds ◽  
Fatty Liver Disease ◽  
Molecular Mechanisms ◽  
Experimental Studies ◽  
Alcoholic Fatty Liver ◽  
Wide Range

Fatty liver disease (FLD), including nonalcoholic fatty liver disease (NAFLD) and alcoholic fatty liver disease (AFLD), is a serious chronic metabolic disease that affects a wide range of people. Lipid accumulation accompanied by oxidative stress and inflammation in the liver is the most important pathogenesis of FLD. The plant-based, high-fiber, and low-fat diet has been recommended to manage FLD for a long time. This review discusses the current state of the art into the effects, mechanisms, and clinical application of plant-based foods in NAFLD and AFLD, with highlighting related molecular mechanisms. Epidemiological evidence revealed that the consumption of several plant-based foods was beneficial to alleviating FLD. Further experimental studies found out that fruits, spices, teas, coffee, and other plants, as well as their bioactive compounds, such as resveratrol, anthocyanin, curcumin, and tea polyphenols, could alleviate FLD by ameliorating hepatic steatosis, oxidative stress, inflammation, gut dysbiosis, and apoptosis, as well as regulating autophagy and ethanol metabolism. More importantly, clinical trials confirmed the beneficial effects of plant-based foods on patients with fatty liver. However, several issues need to be further studied especially the safety and effective doses of plant-based foods and their bioactive compounds. Overall, certain plant-based foods are promising natural sources of bioactive compounds to prevent and alleviate fatty liver disease.

scholarly journals Zyflamend, a Unique Herbal Blend, Inhibits Adipogenesis Through the Coordinated Regulation of PKA and JNK

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 454-454
Author(s):  
Dexter Puckett ◽  
Mohammed Alquraishi ◽  
Samah Chahed ◽  
Dina Alani ◽  
Victoria Frankel ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Lipid Metabolism ◽  
Cell Cycle Progression ◽  
Molecular Mechanisms ◽  
Adipocyte Differentiation ◽  
Kidney Diseases ◽  
Adipogenic Differentiation ◽  
Herbal Extract ◽  
Ampk Signaling

Abstract Objectives The prevalence of obesity and its comorbidities has sparked a worldwide concern to address rates of adipose tissue accrual. Recent studies have demonstrated a novel role of Zyflamend, a natural herbal extract, in regulating lipid metabolism in several cancer cell lines through the activation of the AMPK signaling pathway. Yet, the role of Zyflamend in adipogenic differentiation and lipid metabolism remains largely unexplored. The objective of this study is to investigate the effects of Zyflamend on white 3T3-MBX pre-adipocyte differentiation and elucidate the molecular mechanisms. Methods 3T3-MBX pre-adipocytes were treated with Zyflamend, and the expression of various key adipogenic and lipolytic regulators was examined. We also investigated the effects of Zyflamend on pre-adipocyte survival, proliferation, and cell cycle. Results Zyflamend treatment altered cell cycle progression, attenuated proliferation, and increased cell death of 3T3-MBX pre-adipocytes. In addition, treatment with Zyflamend inhibited lipid accumulation during the differentiation of 3T3-MBX cells, consistent with decreased expression of lipogenic genes and increased lipolysis. Mechanistically, Zyflamend-induced alterations in adipogenesis were mediated, at least in part, through the activation of AMPK, PKA, and JNK. Inhibition of AMPK partially reversed Zyflamend-induced inhibition of differentiation, whereas the inhibition of either JNK or PKA fully restored adipocyte differentiation and decreased lipolysis. Conclusions Taken together, the present study demonstrates that Zyflamend, as a novel anti-adipogenic bioactive mix, inhibits adipocyte differentiation through the activation of PKA and JNK pathways.Our findings suggest that Zyflamend supplementation might help in developing novel anti-obesity therapeutic strategies. Funding Sources This work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (R00DK100736) to A.B.

scholarly journals The Molecular Mechanisms of Iron Metabolism and Its Role in Cardiac Dysfunction and Cardioprotection

2020 ◽  
Vol 21 (21) ◽  
pp. 7889 ◽  
Author(s):  
Tanya Ravingerová ◽  
Lucia Kindernay ◽  
Monika Barteková ◽  
Miroslav Ferko ◽  
Adriana Adameová ◽  
...  
Keyword(s):  
Cell Death ◽  
Iron Metabolism ◽  
Molecular Mechanisms ◽  
Ischemia Reperfusion ◽  
Physiological Role ◽  
Cellular Respiration ◽  
Protective Mechanisms ◽  
Alcoholic Fatty Liver ◽  
Regulated Cell Death ◽  
Wide Range

Iron is an essential mineral participating in different functions of the organism under physiological conditions. Numerous biological processes, such as oxygen and lipid metabolism, protein production, cellular respiration, and DNA synthesis, require the presence of iron, and mitochondria play an important role in the processes of iron metabolism. In addition to its physiological role, iron may be also involved in the adaptive processes of myocardial “conditioning”. On the other hand, disorders of iron metabolism are involved in the pathological mechanisms of the most common human diseases and include a wide range of them, such as type 2 diabetes, obesity, and non-alcoholic fatty liver disease, and accelerate the development of atherosclerosis. Furthermore, iron also exerts potentially deleterious effects that may be manifested under conditions of ischemia/reperfusion (I/R) injury, myocardial infarction, heart failure, coronary artery angioplasty, or heart transplantation, due to its involvement in reactive oxygen species (ROS) production. Moreover, iron has been recently described to participate in the mechanisms of iron-dependent cell death defined as “ferroptosis”. Ferroptosis is a form of regulated cell death that is distinct from apoptosis, necroptosis, and other types of cell death. Ferroptosis has been shown to be associated with I/R injury and several other cardiac diseases as a significant form of cell death in cardiomyocytes. In this review, we will discuss the role of iron in cardiovascular diseases, especially in myocardial I/R injury, and protective mechanisms stimulated by different forms of “conditioning” with a special emphasis on the novel targets for cardioprotection.

scholarly journals Arid1a protects against hepatic steatosis and insulin resistance via PPARα-mediated fatty acid oxidation

2019 ◽  
Author(s):  
Yu-Lan Qu ◽  
Chuan-Huai Deng ◽  
Qing Luo ◽  
Xue-Ying Shang ◽  
Jiao-Xiang Wu ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Fatty Acid ◽  
Hepatic Steatosis ◽  
Fatty Acid Oxidation ◽  
Molecular Mechanisms ◽  
Inflammatory Responses ◽  
Lifestyle Changes ◽  
Health Concern ◽  
Acid Oxidation ◽  
Alcoholic Fatty Liver

AbstractNon-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) have become a worldwide health concern because of lifestyle changes, but it is still lack of specific therapeutic strategies as the underlying molecular mechanisms remain poorly understood. Our previous study indicated that deficiency of Arid1a, a key component of SWI/SNF chromatin remodeling complex, initiated mouse steatohepatitis, implying that Arid1a might be essentially required for the integrity of hepatic lipid metabolism. However, the exact mechanisms of the pathological process due to Arid1a loss are unclear. In the present work, we show that hepatocyte-specific deletion of Arid1a significantly increases susceptibility to develop hepatic steatosis and insulin resistance in mice fed with high-fat diet (HFD), along with the aggravated inflammatory responses marked by increment of serum alanine amino transferase (AST), aspartate amino transferase (AST) and TNFα. Mechanistically, Arid1a deficiency leads to the reduction of chromatin modification characteristic of transcriptional activation on multiple metabolic genes, especially Cpt1a and Acox1, two rate-limiting enzyme genes for fatty acid oxidation. Furthermore, our data indicated that Arid1a loss promotes hepatic steatosis by downregulating PPARα, thereby impairing fatty acid oxidation which leads to lipid accumulation and insulin resistance. These findings reveal that targeting ARID1a might be a promising therapeutic strategy for NAFLD, NASH and insulin resistance.

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