Dynamic repression by BCL6 controls the genome-wide liver response to fasting and steatosis

Transcription is tightly regulated to maintain energy homeostasis during periods of feeding or fasting, but the molecular factors that control these alternating gene programs are incompletely understood. Here, we find that the B cell lymphoma 6 (BCL6) repressor is enriched in the fed state and converges genome-wide with PPARα to potently suppress the induction of fasting transcription. Deletion of hepatocyte Bcl6 enhances lipid catabolism and ameliorates high-fat-diet-induced steatosis. In Ppara-null mice, hepatocyte Bcl6 ablation restores enhancer activity at PPARα-dependent genes and overcomes defective fasting-induced fatty acid oxidation and lipid accumulation. Together, these findings identify BCL6 as a negative regulator of oxidative metabolism and reveal that alternating recruitment of repressive and activating transcription factors to shared cis-regulatory regions dictates hepatic lipid handling.

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IL-15Rα is a determinant of muscle fuel utilization, and its loss protects against obesity

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00505.2014 ◽

2015 ◽

Vol 309 (8) ◽

pp. R835-R844 ◽

Cited By ~ 15

Author(s):

Emanuele Loro ◽

Erin L. Seifert ◽

Cynthia Moffat ◽

Freddy Romero ◽

Manoj K. Mishra ◽

...

Keyword(s):

High Fat Diet ◽

Energy Homeostasis ◽

Wide Distribution ◽

Liver Fat ◽

Acid Oxidation ◽

Direct Effects ◽

High Fat ◽

Binding Partner ◽

Insulin Resistant ◽

Diet Induced Obesity

IL-15Rα is the widely expressed primary binding partner for IL-15. Because of the wide distribution in nonlymphoid tissues like skeletal muscle, adipose, or liver, IL-15/IL-15Rα take part in physiological and metabolic processes not directly related to immunity. In fast muscle, lack of IL-15Rα promotes an oxidative switch, with increased mitochondrial biogenesis and fatigue resistance. These effects are predicted to reproduce some of the benefits of exercise and, therefore, improve energy homeostasis. However, the direct effects of IL-15Rα on metabolism and obesity are currently unknown. We report that mice lacking IL-15Rα (IL-15Rα−/−) are resistant to diet-induced obesity (DIO). High-fat diet-fed IL-15Rα−/− mice have less body and liver fat accumulation than controls. The leaner phenotype is associated with increased energy expenditure and enhanced fatty acid oxidation by muscle mitochondria. Despite being protected against DIO, IL-15Rα−/− are hyperglycemic and insulin-resistant. These findings identify novel roles for IL-15Rα in metabolism and obesity.

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Faculty Opinions recommendation of Genome-wide quantitative enhancer activity maps identified by STARR-seq.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.717973160.793474217 ◽

2013 ◽

Author(s):

Yi Eve Sun ◽

Weihong Ge

Keyword(s):

Enhancer Activity ◽

Genome Wide

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Bcl-2-dependent autophagy disruption during aging impairs amino acid utilization that is restored by hochuekkito

npj Aging and Mechanisms of Disease ◽

10.1038/s41514-021-00065-8 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Miwa Nahata ◽

Sachiko Mogami ◽

Hitomi Sekine ◽

Seiichi Iizuka ◽

Naoto Okubo ◽

...

Keyword(s):

Amino Acid ◽

Energy Homeostasis ◽

Mitochondrial Dynamics ◽

Negative Regulator ◽

Aged Mice ◽

Glucose Levels ◽

Therapeutic Benefits ◽

Age Related ◽

Daily Food ◽

Young Mice

AbstractChronic undernutrition contributes to the increase in frailty observed among elderly adults, which is a pressing issue in the sector of health care for older people worldwide. Autophagy, an intracellular recycling system, is closely associated with age-related pathologies. Therefore, decreased autophagy in aging could be involved in the disruption of energy homeostasis that occurs during undernutrition; however, the physiological mechanisms underlying this process remain unknown. Here, we showed that 70% daily food restriction (FR) induced fatal hypoglycemia in 23–26-month-old (aged) mice, which exhibited significantly lower hepatic autophagy than 9-week-old (young) mice. The liver expressions of Bcl-2, an autophagy-negative regulator, and Beclin1–Bcl-2 binding, were increased in aged mice compared with young mice. The autophagy inducer Tat-Beclin1 D11, not the mTOR inhibitor rapamycin, decreased the plasma levels of the glucogenic amino acid and restored the blood glucose levels in aged FR mice. Decreased liver gluconeogenesis, body temperature, physical activity, amino acid metabolism, and hepatic mitochondrial dynamics were observed in the aged FR mice. These changes were restored by treatment with hochuekkito that is a herbal formula containing several autophagy-activating ingredients. Our results indicate that Bcl-2 upregulation in the liver during the aging process disturbs autophagy activation, which increases the vulnerability to undernutrition. The promotion of liver autophagy may offer clinical therapeutic benefits to frail elderly patients.

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Palmitate reduces starvation-induced ER stress by inhibiting ER-phagy in hypothalamic cells

Molecular Brain ◽

10.1186/s13041-021-00777-8 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Yun Lim ◽

Seolsong Kim ◽

Eun-Kyoung Kim

Keyword(s):

Er Stress ◽

High Fat Diet ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

High Fat ◽

Selective Autophagy ◽

Induced Stress ◽

Hypothalamic Cells ◽

The Brain ◽

Main Region

AbstractPalmitate is a saturated fatty acid that is well known to induce endoplasmic reticulum (ER) stress and autophagy. A high-fat diet increases the palmitate level in the hypothalamus, the main region of the brain regulating energy metabolism. Interestingly, hypothalamic palmitate level is also increased under starvation, urging the study to distinguish the effects of elevated hypothalamic palmitate level under different nutrient conditions. Herein, we show that ER-phagy (ER-targeted selective autophagy) is required for progress of ER stress and that palmitate decreases ER stress by inhibiting ER-phagy in hypothalamic cells under starvation. Palmitate inhibited starvation-induced ER-phagy by increasing the level of B-cell lymphoma 2 (Bcl-2) protein, which inhibits autophagy initiation. These findings suggest that, unlike the induction of ER stress under nutrient-rich conditions, palmitate protects hypothalamic cells from starvation-induced stress by inhibiting ER-phagy.

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Delayed Exercise Training Improves Obesity-Induced Chronic Kidney Disease by Activating AMPK Pathway in High-Fat Diet-Fed Mice

International Journal of Molecular Sciences ◽

10.3390/ijms22010350 ◽

2020 ◽

Vol 22 (1) ◽

pp. 350

Author(s):

Florian Juszczak ◽

Maud Vlassembrouck ◽

Olivia Botton ◽

Thomas Zwakhals ◽

Morgane Decarnoncle ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Exercise Training ◽

High Fat Diet ◽

Interstitial Fibrosis ◽

Calorie Intake ◽

Acid Oxidation ◽

Obese Mice ◽

High Fat ◽

Ampk Pathway

Exercise training is now recognized as an interesting therapeutic strategy in managing obesity and its related disorders. However, there is still a lack of knowledge about its impact on obesity-induced chronic kidney disease (CKD). Here, we investigated the effects of a delayed protocol of endurance exercise training (EET) as well as the underlying mechanism in obese mice presenting CKD. Mice fed a high-fat diet (HFD) or a low-fat diet (LFD) for 12 weeks were subsequently submitted to an 8-weeks EET protocol. Delayed treatment with EET in obese mice prevented body weight gain associated with a reduced calorie intake. EET intervention counteracted obesity-related disorders including glucose intolerance, insulin resistance, dyslipidaemia and hepatic steatosis. Moreover, our data demonstrated for the first time the beneficial effects of EET on obesity-induced CKD as evidenced by an improvement of obesity-related glomerulopathy, tubulo-interstitial fibrosis, inflammation and oxidative stress. EET also prevented renal lipid depositions in the proximal tubule. These results were associated with an improvement of the AMPK pathway by EET in renal tissue. AMPK-mediated phosphorylation of ACC and ULK-1 were particularly enhanced leading to increased fatty acid oxidation and autophagy improvement with EET in obese mice.

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Alterations of 5-hydroxymethylation in circulating cell-free DNA reflect molecular distinctions of subtypes of non-Hodgkin lymphoma

npj Genomic Medicine ◽

10.1038/s41525-021-00179-8 ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Brian C.-H. Chiu ◽

Chang Chen ◽

Qiancheng You ◽

Rudyard Chiu ◽

Girish Venkataraman ◽

...

Keyword(s):

B Cell Lymphoma ◽

Cell Free Dna ◽

Invasive Approach ◽

Non Invasive ◽

Signature Genes ◽

Non Hodgkin Lymphoma ◽

Free Dna ◽

Genome Wide ◽

Circulating Cell Free Dna

AbstractThe 5-methylcytosines (5mC) have been implicated in the pathogenesis of diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). However, the role of 5-hydroxymethylcytosines (5hmC) that are generated from 5mC through active demethylation, in lymphomagenesis is unknown. We profiled genome-wide 5hmC in circulating cell-free DNA (cfDNA) from 73 newly diagnosed patients with DLBCL and FL. We identified 294 differentially modified genes between DLBCL and FL. The differential 5hmC in the DLBCL/FL-differentiating genes co-localized with enhancer marks H3K4me1 and H3K27ac. A four-gene panel (CNN2, HMG20B, ACRBP, IZUMO1) robustly represented the overall 5hmC modification pattern that distinguished FL from DLBCL with an area under curve of 88.5% in the testing set. The median 5hmC modification levels in signature genes showed potential for separating patients for risk of all-cause mortality. This study provides evidence that genome-wide 5hmC profiles in cfDNA differ between DLBCL and FL and could be exploited as a non-invasive approach.

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Genome-wide CRISPR-Cas9 screen identified KLF11 as a druggable suppressor for sarcoma cancer stem cells

Science Advances ◽

10.1126/sciadv.abe3445 ◽

2021 ◽

Vol 7 (5) ◽

pp. eabe3445

Author(s):

Yicun Wang ◽

Jinhui Wu ◽

Hui Chen ◽

Yang Yang ◽

Chengwu Xiao ◽

...

Keyword(s):

Stem Cells ◽

Cancer Stem Cells ◽

Negative Feedback ◽

Direct Interaction ◽

Therapy Resistance ◽

Negative Regulator ◽

Chemotherapy Response ◽

Genome Wide

Cancer stem cells (CSCs) are involved in tumorigenesis, recurrence, and therapy resistance. To identify critical regulators of sarcoma CSCs, we performed a reporter-based genome-wide CRISPR-Cas9 screen and uncovered Kruppel-like factor 11 (KLF11) as top candidate. In vitro and in vivo functional annotation defined a negative role of KLF11 in CSCs. Mechanistically, KLF11 and YAP/TEAD bound to adjacent DNA sites along with direct interaction. KLF11 recruited SIN3A/HDAC to suppress the transcriptional output of YAP/TEAD, which, in turn, promoted KLF11 transcription, forming a negative feedback loop. However, in CSCs, this negative feedback was lost because of epigenetic silence of KLF11, causing sustained YAP activation. Low KLF11 was associated with poor prognosis and chemotherapy response in patients with sarcoma. Pharmacological activation of KLF11 by thiazolidinedione effectively restored chemotherapy response. Collectively, our study identifies KLF11 as a negative regulator in sarcoma CSCs and potential therapeutic target.

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TAMI-35. AUTOPHAGY MEDIATED LIPID CATABOLISM FACILITATES GLIOMA PROGRESSION TO OVERCOME BIOENERGETIC CRISIS

Neuro-Oncology ◽

10.1093/neuonc/noaa215.923 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii220-ii220

Author(s):

Chenran Wang ◽

Michael Haas ◽

Syn Yeo ◽

Ritama Paul ◽

Fuchun Yang ◽

...

Keyword(s):

Tumor Progression ◽

Cancer Cells ◽

Strong Association ◽

Glioma Cells ◽

Acid Oxidation ◽

Mrna Levels ◽

Atp Production ◽

Lipid Catabolism ◽

Mtorc1 Signaling

Abstract Activation of mTORC1 plays a significant role in cancer development and progression. However, the metabolic mechanisms to sustain mTORC1 activation in stressed cancer cells are still underappreciated. Autophagy, one downstream process of mTORC1, is proposed to be suppressed under the condition of mTORC1 hyper-activation. Interestingly, we recently revealed higher autophagy activity in various Tsc-deficient tumor cells with mTORC1 hyper-activity. Nevertheless, the functions and mechanisms of autophagy in regulating mTORC1 in cancer cells are not well understood. In this study, we revealed a strong association of altered mRNA levels in mTORC1 upstream and downstream genes with poor prognosis of glioma patients. Our metabolic and molecular studies indicated that autophagy mediated lipid catabolism was essential to sustain mTORC1 activity in glioma cells under energy stresses. We found that autophagy inhibitors or fatty acid oxidation (FAO) inhibition in combination with 2-Deoxy-D-glucose (2DG) decreased oxidative phosphorylation, ATP production, mTORC1 activity, and survival of glioma cells in vitro. Consistently, the combination of chloroquine (CQ) or FAO inhibitors with 2DG effectively suppressed the progression of xenografted glioma with mTORC1 hyperactivation in mice. This study established a novel autophagy/lipid degradation/FAO/ATP pathway that maintains high mTORC1 signaling and tumor progression in brain cancer cells under energy stresses. The requirement of lipophagy in brain cancers may provide an opportunity to develop new molecular therapeutic targets to counteract mTORC1 for tumor progression.

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