Inhibition of Bromodomain and Extraterminal Domain (BET) Proteins by JQ1 Unravels a Novel Epigenetic Modulation to Control Lipid Homeostasis

The homeostatic control of lipid metabolism is essential for many fundamental physiological processes. A deep understanding of its regulatory mechanisms is pivotal to unravel prospective physiopathological factors and to identify novel molecular targets that could be employed to design promising therapies in the management of lipid disorders. Here, we investigated the role of bromodomain and extraterminal domain (BET) proteins in the regulation of lipid metabolism. To reach this aim, we used a loss-of-function approach by treating HepG2 cells with JQ1, a powerful and selective BET inhibitor. The main results demonstrated that BET inhibition by JQ1 efficiently decreases intracellular lipid content, determining a significant modulation of proteins involved in lipid biosynthesis, uptake and intracellular trafficking. Importantly, the capability of BET inhibition to slow down cell proliferation is dependent on the modulation of cholesterol metabolism. Taken together, these data highlight a novel epigenetic mechanism involved in the regulation of lipid homeostasis.

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High Fat Activates O-GlcNAcylation and Affects AMPK/ACC Pathway to Regulate Lipid Metabolism

Nutrients ◽

10.3390/nu13061740 ◽

2021 ◽

Vol 13 (6) ◽

pp. 1740

Author(s):

Yuning Pang ◽

Xiang Xu ◽

Xiaojun Xiang ◽

Yongnan Li ◽

Zengqi Zhao ◽

...

Keyword(s):

Lipid Metabolism ◽

High Fat Diet ◽

Lipid Synthesis ◽

Fat Deposition ◽

Liver Fat ◽

Lipid Homeostasis ◽

High Fat ◽

Dual Inhibitor ◽

Regulate Lipid Metabolism

A high-fat diet often leads to excessive fat deposition and adversely affects the organism. However, the mechanism of liver fat deposition induced by high fat is still unclear. Therefore, this study aimed at acetyl-CoA carboxylase (ACC) to explore the mechanism of excessive liver deposition induced by high fat. In the present study, the ORF of ACC1 and ACC2 were cloned and characterized. Meanwhile, the mRNA and protein of ACC1 and ACC2 were increased in liver fed with a high-fat diet (HFD) or in hepatocytes incubated with oleic acid (OA). The phosphorylation of ACC was also decreased in hepatocytes incubated with OA. Moreover, AICAR dramatically improved the phosphorylation of ACC, and OA significantly inhibited the phosphorylation of the AMPK/ACC pathway. Further experiments showed that OA increased global O-GlcNAcylation and agonist of O-GlcNAcylation significantly inhibited the phosphorylation of AMPK and ACC. Importantly, the disorder of lipid metabolism caused by HFD or OA could be rescued by treating CP-640186, the dual inhibitor of ACC1 and ACC2. These observations suggested that high fat may activate O-GlcNAcylation and affect the AMPK/ACC pathway to regulate lipid synthesis, and also emphasized the importance of the role of ACC in lipid homeostasis.

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Circadian clock control of hepatic lipid metabolism: role of small heterodimer partner (Shp)

Journal of Investigative Medicine ◽

10.1136/jim-2016-000194 ◽

2016 ◽

Vol 64 (7) ◽

pp. 1158-1161 ◽

Cited By ~ 3

Author(s):

Li Wang ◽

Suthat Liangpunsakul

Keyword(s):

Lipid Metabolism ◽

Hepatic Steatosis ◽

Lipid Homeostasis ◽

Pas Domain ◽

Hepatic Lipid Metabolism ◽

Small Heterodimer Partner ◽

Excessive Alcohol ◽

Review Reports ◽

Clock Mechanism

Hepatic steatosis, the accumulation of triglyceride droplets in the hepatocytes, is a common hepatic pathology seen in subjects with obesity/metabolic syndrome and those with excessive alcohol use. The pathogenesis underlying hepatic steatosis is complex. Recent studies have shown the specific role played by the molecular clock mechanism in the control of lipid metabolism and that the disruption of these tissue clocks may lead to the disturbances in lipid homeostasis. This review reports a novel role of small heterodimer partner in maintaining triglyceride and lipoprotein homeostasis through neuronal PAS domain protein 2.

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

International Journal of Molecular Sciences ◽

10.3390/ijms21062061 ◽

2020 ◽

Vol 21 (6) ◽

pp. 2061 ◽

Cited By ~ 13

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.

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Loss of Mrap2 is associated with Sim1 deficiency and increased circulating cholesterol

Journal of Endocrinology ◽

10.1530/joe-16-0057 ◽

2016 ◽

Vol 230 (1) ◽

pp. 13-26 ◽

Cited By ~ 23

Author(s):

T V Novoselova ◽

R Larder ◽

D Rimmington ◽

C Lelliott ◽

E H Wynn ◽

...

Keyword(s):

Lipid Metabolism ◽

Metabolic Regulation ◽

Energy Homeostasis ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Melanocortin Receptor ◽

Accessory Protein ◽

Loss Of Function ◽

Deficient Mice

Melanocortin receptor accessory protein 2 (MRAP2) is a transmembrane accessory protein predominantly expressed in the brain. Both global and brain-specific deletion of Mrap2 in mice results in severe obesity. Loss-of-function MRAP2 mutations have also been associated with obesity in humans. Although MRAP2 has been shown to interact with MC4R, a G protein-coupled receptor with an established role in energy homeostasis, appetite regulation and lipid metabolism, the mechanisms through which loss of MRAP2 causes obesity remains uncertain. In this study, we used two independently derived lines of Mrap2 deficient mice (Mrap2tm1a/tm1a) to further study the role of Mrap2 in the regulation of energy balance and peripheral lipid metabolism. Mrap2tm1a/tm1a mice have a significant increase in body weight, with increased fat and lean mass, but without detectable changes in food intake or energy expenditure. Transcriptomic analysis showed significantly decreased expression of Sim1, Trh, Oxt and Crh within the hypothalamic paraventricular nucleus of Mrap2tm1a/tm1a mice. Circulating levels of both high-density lipoprotein and low-density lipoprotein were significantly increased in Mrap2 deficient mice. Taken together, these data corroborate the role of MRAP2 in metabolic regulation and indicate that, at least in part, this may be due to defective central melanocortin signalling.

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Linking Gut Microbiome and Lipid Metabolism: Moving beyond Associations

Metabolites ◽

10.3390/metabo11010055 ◽

2021 ◽

Vol 11 (1) ◽

pp. 55

Author(s):

Santosh Lamichhane ◽

Partho Sen ◽

Marina Amaral Alves ◽

Henrique C. Ribeiro ◽

Peppi Raunioniemi ◽

...

Keyword(s):

Lipid Metabolism ◽

Gut Microbiome ◽

Systemic Circulation ◽

Water Soluble ◽

Lipid Homeostasis ◽

Microbial Lipids ◽

Human Gut ◽

Polar Metabolites ◽

Health And Disease

Various studies aiming to elucidate the role of the gut microbiome-metabolome co-axis in health and disease have primarily focused on water-soluble polar metabolites, whilst non-polar microbial lipids have received less attention. The concept of microbiota-dependent lipid biotransformation is over a century old. However, only recently, several studies have shown how microbial lipids alter intestinal and circulating lipid concentrations in the host, thus impacting human lipid homeostasis. There is emerging evidence that gut microbial communities play a particularly significant role in the regulation of host cholesterol and sphingolipid homeostasis. Here, we review and discuss recent research focusing on microbe-host-lipid co-metabolism. We also discuss the interplay of human gut microbiota and molecular lipids entering host systemic circulation, and its role in health and disease.

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Lnc027912 Reduces Lipid Accumulation Through Akt/MTOR/SREBP1C Axis in Hepatic Cells

10.21203/rs.3.rs-1218577/v1 ◽

2022 ◽

Author(s):

Kaifei Chu ◽

Niannian Zhao ◽

Rong Feng ◽

Li Zhang ◽

Xudong Hu ◽

...

Keyword(s):

Lipid Metabolism ◽

Western Blot ◽

Lipid Accumulation ◽

Cholesterol Metabolism ◽

Cell Model ◽

Luciferase Reporter ◽

Hepatic Cells ◽

Gene Assay ◽

Signaling Axis

Abstract Background: Various metabolism diseases are closely related to lipid metabolism disorder, but long noncoding-RNAs (lncRNA) involve in regulating function of lipid was limited elucidated. Previous our work have found that lnc027912 involve in cholesterol metabolism. Here, we further explore the role of lipid metabolism-associated lncRNA-lnc027912 in oleic acid- (OA) and palmitic acid (PA)-induced hepatic cells. Methods: The overexpression of lnc027912 cell model was constructed by using virus particles transfection, and the level of lnc027912 in AML12 cells were detected by RT-qPCR. High fat cell model was established by treating AML12 cells with OA and PA, and the level of lipid drops was detected by Oil red O staining and triglyceride analyze Kit. The lipid metabolism related-genes, such as SREBP1C, FAS, PPARγ, MTTP, ApoE and ApoC3 level, was detected using RT-qPCR and Western blot. The role of SREBP1C in lipid metabolism was further analyzed using double luciferase reporter gene assay and Immunofluorescence. The Akt/mTOR signal pathway related genes was detected by Western blot. Results: We found that TG level was inhibited in overexpression of lnc027912 cell. Upregulated lnc027912 of AML12 cells treated with OA and PA showed a significant decrease in lipid accumulation and TG levels. Furthermore, overexpression of lnc027912, the lipid biosynthesis genes of SREBP1C, FAS and PPARγ was significantly decreased and a significant increase in expression of MTTP and ApoE. Interestingly, lnc027912 inhibited Akt/mTOR signaling axis and decreased SREBP1C transit into nucleus and the promoter activity of SREBP1C and regulated expression of its targets. Conclusions: Our study revealed a new insights into the molecular function of lnc027912 in lipid metabolism by Akt/mTOR/SREBP1C signaling axis and highlights the potential of lnc027912 as a new therapeutic target for lipid disorder diseases (such as, NAFLD).

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Loss-of-function mutation in Pcsk1 increases serum APOA1 level and LCAT activity in mice

Laboratory Animal Research ◽

10.1186/s42826-021-00111-2 ◽

2022 ◽

Vol 38 (1) ◽

Author(s):

Aleksandra Aljakna Khan ◽

Nakyung Kim ◽

Ron Korstanje ◽

Seungbum Choi

Keyword(s):

Cholesterol Metabolism ◽

Wide Spectrum ◽

Hdl Cholesterol ◽

Apolipoprotein A1 ◽

Cholesterol Concentration ◽

Lcat Activity ◽

Loss Of Function ◽

Nucleotide Mutation ◽

Hdl Metabolism

Abstract Background The convertase subtilisin/kexin family 1 gene (PCSK1) has been associated in various human genetics studies with a wide spectrum of metabolic phenotypes, including early-onset obesity, hyperphagia, diabetes insipidus, and others. Despite the evident influence of PCSK1 on obesity and the known functions of other PCSKs in lipid metabolism, the role of PCSK1 specifically in lipid and cholesterol metabolism remains unclear. This study evaluated the effect of loss of PCSK1 function on high-density lipoprotein (HDL) metabolism in mice. Results HDL cholesterol, apolipoprotein A1 (APOA1) levels in serum and liver, and the activities of two enzymes (lecithin-cholesterol acyltransferase, LCAT and phospholipid transfer protein, PLTP) were evaluated in 8-week-old mice with a non-synonymous single nucleotide mutation leading to an amino acid substitution in PCSK1, which results in a loss of protein’s function. Mutant mice had similar serum HDL cholesterol concentration but increased levels of serum total and mature APOA1, and LCAT activity in comparison to controls. Conclusions This study presents the first evaluation of the role of PCSK1 in HDL metabolism using a loss-of-function mutant mouse model. Further investigations will be needed to determine the underlying molecular mechanism.

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Lipin-1, a Versatile Regulator of Lipid Homeostasis, Is a Potential Target for Fighting Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms22094419 ◽

2021 ◽

Vol 22 (9) ◽

pp. 4419

Author(s):

Laura Brohée ◽

Julie Crémer ◽

Alain Colige ◽

Christophe Deroanne

Keyword(s):

Lipid Metabolism ◽

Tumor Microenvironment ◽

Adjuvant Therapy ◽

Cancer Cells ◽

Therapeutic Strategy ◽

Lipid Homeostasis ◽

Cancer Therapies ◽

Anti Cancer ◽

Lipin 1

The rewiring of lipid metabolism is a major adaptation observed in cancer, and it is generally associated with the increased aggressiveness of cancer cells. Targeting lipid metabolism is therefore an appealing therapeutic strategy, but it requires a better understanding of the specific roles played by the main enzymes involved in lipid biosynthesis. Lipin-1 is a central regulator of lipid homeostasis, acting either as an enzyme or as a co-regulator of transcription. In spite of its important functions it is only recently that several groups have highlighted its role in cancer. Here, we will review the most recent research describing the role of lipin-1 in tumor progression when expressed by cancer cells or cells of the tumor microenvironment. The interest of its inhibition as an adjuvant therapy to amplify the effects of anti-cancer therapies will be also illustrated.

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Comparative studies on phospholipase A2 as a marker for the gut microbiota-liver-brain axis in a rodent model of autism.

Current Proteomics ◽

10.2174/1570164617999200519100634 ◽

2020 ◽

Vol 17 ◽

Author(s):

Abeer Al-Dbass ◽

Abir Ben Bacha ◽

Nadine MS Moubayed ◽

Ramesa Shafi Bhat ◽

Manar Al-Mutairi ◽

...

Keyword(s):

Lipid Metabolism ◽

Treatment Group ◽

Vitamin B12 ◽

Phospholipase A2 ◽

Combined Treatment ◽

Lipid Homeostasis ◽

Control Group ◽

Peripheral Tissues ◽

Group I

Background: Lipid homeostasis and gut flora can be related to many metabolic diseases, especially autism. Lipid metabolism in the brain can control neuronal structure and function and can also take part in signal transduction pathways to control metabolism in peripheral tissues, especially in the liver. Impaired phospholipid metabolism promotes oxidative stress and neuroinflammation and is therefore directly related to autism. Objective: The effect of propionic acid (PPA) toxicity on lipid homeostasis in the gut-liver-brain axis was evaluated to understand their inter-connection. Cytosolic phospholipase A2 (cPLA2) concentration and activity was measured in autistic model and protective role of omega-3 (ω-3) and vitamin B12 was evaluated. Methods: Animals were divided into five groups: Group I (control group); Group II (autistic model treated with neurotoxic dose of PPA); Group III (treated with vitamin B12 (16.7 mg/kg/day) for 30 days post PPA treatment); Group IV (treated with ω-3 (200 mg/kg body weight/day) for 30 days post PPA treatment ;Group V (combined dose of ω-3 and Vitamin B12, for 30 days post PPA treatment). Phospholipase A2 activity and protein expression level in the liver homogenate of all the groups was analyzed by western blotting and was compared to brain cPLA2. Results: PPA increased the levels of liver and brain cPLA2. However, independent or combined treatment with ω-3 and vitamin B12 was effective in neutralizing its effect. Moreover, PPA-induced dysbiosis, which was ameliorated with the above treatments. Conclusions: This study showed the role of cPLA2 as a lipid metabolism marker, related to PPA-induced inflammation through a highly interactive gut-liver-brain axis.

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Estrogen Receptor beta (ERβ) Regulation of Lipid Homeostasis—Does Sex Matter?

Metabolites ◽

10.3390/metabo10030116 ◽

2020 ◽

Vol 10 (3) ◽

pp. 116 ◽

Cited By ~ 2

Author(s):

Christina Savva ◽

Marion Korach-André

Keyword(s):

Estrogen Receptor ◽

Sex Differences ◽

Lipid Metabolism ◽

Estrogen Receptor Beta ◽

Lipid Homeostasis ◽

Special Focus ◽

Dependent Manner ◽

Selective Targeting ◽

Receptor Beta

In this communication, we aim to summarize the role of estrogen receptor beta (ERβ) in lipid metabolism in the main metabolic organs with a special focus on sex differences. The action of ERβ is tissue-specific and acts in a sex-dependent manner, emphasizing the necessity of developing sex- and tissue-selective targeting drugs in the future.

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