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Article ; Online: The circadian clock and cancer: links between circadian disruption and disease Pathology.

Fekry, Baharan / Eckel-Mahan, Kristin

2022 Volume 171, Issue 5, Page(s) 477–486

Abstract: There is growing evidence that disruption of our 24-h clock increases our risk for acquiring several diseases and disorders. One of these diseases is cancer. While the mechanistic links between circadian clock disruption and cancer initiation or ... ...

Abstract	There is growing evidence that disruption of our 24-h clock increases our risk for acquiring several diseases and disorders. One of these diseases is cancer. While the mechanistic links between circadian clock disruption and cancer initiation or progression are an active area of study, significantly more work needs to be done to understand the molecular substrates involved. Of particular complexity remains the functions of the clock in individual cells during the process of transformation (cancer initiation) versus the functions of the clock in tumour-surrounding stroma in the process of tumour progression or metastasis. Indeed, the nexus of cellular circadian dynamics, metabolism and carcinogenesis is drawing more attention, and many new studies are now highlighting the critical role of circadian rhythms and clock proteins in cancer prevention. In this brief review, we cover some of the basic mechanisms reported to link circadian disruption and cancer at the level of gene expression and metabolism. We also review some of the human studies addressing circadian disruption and cancer incidence as well as some controlled laboratory studies connecting the two in pre-clinical models. Finally, we discuss the tremendous opportunity to use circadian approaches for future prevention and treatment in the context of cancer in specific organs.
MeSH term(s)	Carcinogenesis/genetics ; Circadian Clocks/genetics ; Circadian Rhythm/genetics ; Humans ; Neoplasms/metabolism
Language	English
Publishing date	2022-03-14
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	218073-x
ISSN	1756-2651 ; 0021-924X
ISSN (online)	1756-2651
ISSN	0021-924X
DOI	10.1093/jb/mvac017
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Article ; Online: Expression of p-STAT3 and c-Myc correlates with P2-HNF4α expression in nonalcoholic fatty liver disease (NAFLD).

Younes, Mamoun / Zhang, Lin / Fekry, Baharan / Eckel-Mahan, Kristin

Oncotarget

2022 Volume 13, Page(s) 1308–1313

Abstract: We studied the expression of two hepatocyte nuclear factor 4 alpha (HNF4α) isoforms, p-STAT3. and c-Myc in 49 consecutive liver biopsies with nonalcoholic fatty liver disease (NAFLD) using immunohistochemistry. All 49 biopsies (100%) were positive for ... ...

Abstract	We studied the expression of two hepatocyte nuclear factor 4 alpha (HNF4α) isoforms, p-STAT3. and c-Myc in 49 consecutive liver biopsies with nonalcoholic fatty liver disease (NAFLD) using immunohistochemistry. All 49 biopsies (100%) were positive for nuclear expression of P1-HNF4α. Twenty-eight (57%) cases were positive for P2-HNF4α, 6 (12%) were positive for p-STAT3 and 5 (10%) were positive for c-Myc. All 6 (100%) p-STAT3-positive cases were also positive for P2-HNF4α (
MeSH term(s)	Humans ; Non-alcoholic Fatty Liver Disease ; Fibrosis ; Hypertension ; STAT3 Transcription Factor
Chemical Substances	STAT3 protein, human ; STAT3 Transcription Factor
Language	English
Publishing date	2022-12-06
Publishing country	United States
Document type	Journal Article
ZDB-ID	2560162-3
ISSN	1949-2553 ; 1949-2553
ISSN (online)	1949-2553
ISSN	1949-2553
DOI	10.18632/oncotarget.28324
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Article ; Online: Clocks and Cholesterol: Co-agonists in Cardiovascular Disease?

Fekry, Baharan / Eckel-Mahan, Kristin

EBioMedicine

2017 Volume 20, Page(s) 5–6

Language	English
Publishing date	2017-06
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2851331-9
ISSN	2352-3964
ISSN (online)	2352-3964
DOI	10.1016/j.ebiom.2017.05.021
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Article ; Online: Circadian Clock and Complement Immune System-Complementary Control of Physiology and Pathology?

Shivshankar, Pooja / Fekry, Baharan / Eckel-Mahan, Kristin / Wetsel, Rick A

Frontiers in cellular and infection microbiology

2020 Volume 10, Page(s) 418

Abstract: Mammalian species contain an internal circadian (i.e., 24-h) clock that is synchronized to the day and night cycles. Large epidemiological studies, which are supported by carefully controlled studies in numerous species, support the idea that chronic ... ...

Abstract	Mammalian species contain an internal circadian (i.e., 24-h) clock that is synchronized to the day and night cycles. Large epidemiological studies, which are supported by carefully controlled studies in numerous species, support the idea that chronic disruption of our circadian cycles results in a number of health issues, including obesity and diabetes, defective immune response, and cancer. Here we focus specifically on the role of the complement immune system and its relationship to the internal circadian clock system. While still an incompletely understood area, there is evidence that dysregulated proinflammatory cytokines, complement factors, and oxidative stress can be induced by circadian disruption and that these may feed back into the oscillator at the level of circadian gene regulation. Such a feedback cycle may contribute to impaired host immune response against pathogenic insults. The complement immune system including its activated anaphylatoxins, C3a and C5a, not only facilitate innate and adaptive immune response in chemotaxis and phagocytosis, but they can also amplify chronic inflammation in the host organism. Consequent development of autoimmune disorders, and metabolic diseases associated with additional environmental insults that activate complement can in severe cases, lead to accelerated tissue dysfunction, fibrosis, and ultimately organ failure. Because several promising complement-targeted therapeutics to block uncontrolled complement activation and treat autoimmune diseases are in various phases of clinical trials, understanding fully the circadian properties of the complement system, and the reciprocal regulation by these two systems could greatly improve patient treatment in the long term.
MeSH term(s)	Anaphylatoxins ; Animals ; Circadian Clocks ; Complement System Proteins ; Humans ; Immune System ; Immunity
Chemical Substances	Anaphylatoxins ; Complement System Proteins (9007-36-7)
Language	English
Publishing date	2020-08-14
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2619676-1
ISSN	2235-2988 ; 2235-2988
ISSN (online)	2235-2988
ISSN	2235-2988
DOI	10.3389/fcimb.2020.00418
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Article ; Online: Feasible diet and circadian interventions reduce in vivo progression of FLT3-ITD-positive acute myeloid leukemia.

Cancer medicine

2024 Volume 13, Issue 2, Page(s) e6949

Abstract: Background: Acute myeloid leukemia (AML) with an internal tandem duplication in the fms-like tyrosine kinase receptor 3 gene (FLT3-ITD) is associated with poor survival, and few studies have examined the impact of modifiable behaviors, such as nutrient ... ...

Abstract	Background: Acute myeloid leukemia (AML) with an internal tandem duplication in the fms-like tyrosine kinase receptor 3 gene (FLT3-ITD) is associated with poor survival, and few studies have examined the impact of modifiable behaviors, such as nutrient quality and timing, in this subset of acute leukemia. Methods: The influence of diet composition (low-sucrose and/or low-fat diets) and timing of diet were tested in tandem with anthracycline treatment in orthotopic xenograft mouse models. A pilot clinical study to test receptivity of pediatric leukemia patients to macronutrient matched foods was conducted. A role for the circadian protein, BMAL1 (brain and muscle ARNT-like 1), in effects of diet timing was studied by overexpression in FLT3-ITD-bearing AML cells. Results: Reduced tumor burden in FLT3-ITD AML-bearing mice was observed with interventions utilizing low-sucrose and/or low-fat diets, or time-restricted feeding (TRF) compared to mice fed normal chow ad libitum. In a tasting study, macronutrient matched low-sucrose and low-fat meals were offered to pediatric acute leukemia patients who largely reported liking the meals. Expression of the circadian protein, BMAL1, was heightened with TRF and the low-sucrose diet. BMAL1 overexpression and treatment with a pharmacological inducer of BMAL1 was cytotoxic to FLT3-ITD AML cells. Conclusions: Mouse models for FLT3-ITD AML show that diet composition and timing slows progression of FLT3-ITD AML growth in vivo, potentially mediated by BMAL1. These interventions to enhance therapy efficacy show preliminary feasibility, as pediatric leukemia patients responded favorable to preparation of macronutrient matched meals.
MeSH term(s)	Humans ; Child ; Mice ; Animals ; ARNTL Transcription Factors/genetics ; Leukemia, Myeloid, Acute/therapy ; Leukemia, Myeloid, Acute/drug therapy ; Antineoplastic Agents/therapeutic use ; Disease Models, Animal ; Diet ; Sucrose/therapeutic use ; fms-Like Tyrosine Kinase 3/genetics ; Mutation
Chemical Substances	ARNTL Transcription Factors ; Antineoplastic Agents ; Sucrose (57-50-1) ; fms-Like Tyrosine Kinase 3 (EC 2.7.10.1) ; FLT3 protein, human (EC 2.7.10.1)
Language	English
Publishing date	2024-02-09
Publishing country	United States
Document type	Journal Article
ZDB-ID	2659751-2
ISSN	2045-7634 ; 2045-7634
ISSN (online)	2045-7634
ISSN	2045-7634
DOI	10.1002/cam4.6949
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Article ; Online: Interfering with lipid metabolism through targeting CES1 sensitizes hepatocellular carcinoma for chemotherapy.

Li, Gang / Li, Xin / Mahmud, Iqbal / Ysaguirre, Jazmin / Fekry, Baharan / Wang, Shuyue / Wei, Bo / Eckel-Mahan, Kristin L / Lorenzi, Philip L / Lehner, Richard / Sun, Kai

JCI insight

2023 Volume 8, Issue 2

Abstract: Hepatocellular carcinoma (HCC) is the most common lethal form of liver cancer. Apart from surgical removal and transplantation, other treatments have not yet been well established for patients with HCC. In this study, we found that carboxylesterase 1 ( ... ...

Abstract	Hepatocellular carcinoma (HCC) is the most common lethal form of liver cancer. Apart from surgical removal and transplantation, other treatments have not yet been well established for patients with HCC. In this study, we found that carboxylesterase 1 (CES1) is expressed at various levels in HCC. We further revealed that blockage of CES1 by pharmacological and genetical approaches leads to altered lipid profiles that are directly linked to impaired mitochondrial function. Mechanistically, lipidomic analyses indicated that lipid signaling molecules, including polyunsaturated fatty acids (PUFAs), which activate PPARα/γ, were dramatically reduced upon CES1 inhibition. As a result, the expression of SCD, a PPARα/γ target gene involved in tumor progression and chemoresistance, was significantly downregulated. Clinical analysis demonstrated a strong correlation between the protein levels of CES1 and SCD in HCC. Interference with lipid signaling by targeting the CES1-PPARα/γ-SCD axis sensitized HCC cells to cisplatin treatment. As a result, the growth of HCC xenograft tumors in NU/J mice was potently slowed by coadministration of cisplatin and CES1 inhibition. Our results, thus, suggest that CES1 is a promising therapeutic target for HCC treatment.
MeSH term(s)	Humans ; Mice ; Animals ; Carcinoma, Hepatocellular/genetics ; Liver Neoplasms/genetics ; Lipid Metabolism/genetics ; Cisplatin/therapeutic use ; PPAR alpha/metabolism ; Lipids ; Carboxylic Ester Hydrolases/genetics ; Carboxylic Ester Hydrolases/metabolism ; Carboxylic Ester Hydrolases/therapeutic use
Chemical Substances	Cisplatin (Q20Q21Q62J) ; PPAR alpha ; Lipids ; CES1 protein, human (EC 3.1.1.1) ; Carboxylic Ester Hydrolases (EC 3.1.1.-)
Language	English
Publishing date	2023-01-24
Publishing country	United States
Document type	Journal Article
ISSN	2379-3708
ISSN (online)	2379-3708
DOI	10.1172/jci.insight.163624
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Article: HNF4α isoforms regulate the circadian balance between carbohydrate and lipid metabolism in the liver.

Deans, Jonathan R / Deol, Poonamjot / Titova, Nina / Radi, Sarah H / Vuong, Linh M / Evans, Jane R / Pan, Songqin / Fahrmann, Johannes / Yang, Jun / Hammock, Bruce D / Fiehn, Oliver / Fekry, Baharan / Eckel-Mahan, Kristin / Sladek, Frances M

Frontiers in endocrinology

2023 Volume 14, Page(s) 1266527

Abstract: Hepatocyte Nuclear Factor 4α (HNF4α), a master regulator of hepatocyte differentiation, is regulated by two promoters (P1 and P2) which drive the expression of different isoforms. P1-HNF4α is the major isoform in the adult liver while P2-HNF4α is thought ...

Abstract	Hepatocyte Nuclear Factor 4α (HNF4α), a master regulator of hepatocyte differentiation, is regulated by two promoters (P1 and P2) which drive the expression of different isoforms. P1-HNF4α is the major isoform in the adult liver while P2-HNF4α is thought to be expressed only in fetal liver and liver cancer. Here, we show that P2-HNF4α is indeed expressed in the normal adult liver at Zeitgeber time (ZT)9 and ZT21. Using exon swap mice that express only P2-HNF4α we show that this isoform orchestrates a distinct transcriptome and metabolome via unique chromatin and protein-protein interactions, including with different clock proteins at different times of the day leading to subtle differences in circadian gene regulation. Furthermore, deletion of the
MeSH term(s)	Animals ; Female ; Mice ; Carbohydrates ; Hepatocyte Nuclear Factor 4/genetics ; Hepatocyte Nuclear Factor 4/metabolism ; Lipid Metabolism/genetics ; Liver/metabolism ; Protein Isoforms/genetics ; Protein Isoforms/metabolism
Chemical Substances	Carbohydrates ; Hepatocyte Nuclear Factor 4 ; Protein Isoforms ; Hnf4a protein, mouse
Language	English
Publishing date	2023-12-04
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, Non-U.S. Gov't
ZDB-ID	2592084-4
ISSN	1664-2392
ISSN	1664-2392
DOI	10.3389/fendo.2023.1266527
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Article ; Online: Interfering with lipid metabolism through targeting CES1 sensitizes hepatocellular carcinoma for chemotherapy

Gang Li / Xin Li / Iqbal Mahmud / Jazmin Ysaguirre / Baharan Fekry / Shuyue Wang / Bo Wei / Kristin L. Eckel-Mahan / Philip L. Lorenzi / Richard Lehner / Kai Sun

JCI Insight, Vol 8, Iss

2023 Volume 2

Abstract	Hepatocellular carcinoma (HCC) is the most common lethal form of liver cancer. Apart from surgical removal and transplantation, other treatments have not yet been well established for patients with HCC. In this study, we found that carboxylesterase 1 (CES1) is expressed at various levels in HCC. We further revealed that blockage of CES1 by pharmacological and genetical approaches leads to altered lipid profiles that are directly linked to impaired mitochondrial function. Mechanistically, lipidomic analyses indicated that lipid signaling molecules, including polyunsaturated fatty acids (PUFAs), which activate PPARα/γ, were dramatically reduced upon CES1 inhibition. As a result, the expression of SCD, a PPARα/γ target gene involved in tumor progression and chemoresistance, was significantly downregulated. Clinical analysis demonstrated a strong correlation between the protein levels of CES1 and SCD in HCC. Interference with lipid signaling by targeting the CES1-PPARα/γ-SCD axis sensitized HCC cells to cisplatin treatment. As a result, the growth of HCC xenograft tumors in NU/J mice was potently slowed by coadministration of cisplatin and CES1 inhibition. Our results, thus, suggest that CES1 is a promising therapeutic target for HCC treatment.
Keywords	Metabolism ; Medicine ; R
Language	English
Publishing date	2023-08-01T00:00:00Z
Publisher	American Society for Clinical investigation
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Adipose tissue-specific ablation of Ces1d causes metabolic dysregulation in mice.

Li, Gang / Li, Xin / Yang, Li / Wang, Shuyue / Dai, Yulin / Fekry, Baharan / Veillon, Lucas / Tan, Lin / Berdeaux, Rebecca / Eckel-Mahan, Kristin / Lorenzi, Philip L / Zhao, Zhongming / Lehner, Richard / Sun, Kai

Life science alliance

2022 Volume 5, Issue 8

Abstract: Carboxylesterase 1d (Ces1d) is a crucial enzyme with a wide range of activities in multiple tissues. It has been reported to localize predominantly in ER. Here, we found that Ces1d levels are significantly increased in obese patients with type 2 diabetes. ...

Abstract	Carboxylesterase 1d (Ces1d) is a crucial enzyme with a wide range of activities in multiple tissues. It has been reported to localize predominantly in ER. Here, we found that Ces1d levels are significantly increased in obese patients with type 2 diabetes. Intriguingly, a high level of Ces1d translocates onto lipid droplets where it digests the lipids to produce a unique set of fatty acids. We further revealed that adipose tissue-specific Ces1d knock-out (FKO) mice gained more body weight with increased fat mass during a high fat-diet challenge. The FKO mice exhibited impaired glucose and lipid metabolism and developed exacerbated liver steatosis. Mechanistically, deficiency of Ces1d induced abnormally large lipid droplet deposition in the adipocytes, causing ectopic accumulation of triglycerides in other peripheral tissues. Furthermore, loss of Ces1d diminished the circulating free fatty acids serving as signaling molecules to trigger the epigenetic regulations of energy metabolism via lipid-sensing transcriptional factors, such as HNF4α. The metabolic disorders induced an unhealthy microenvironment in the metabolically active tissues, ultimately leading to systemic insulin resistance.
MeSH term(s)	Adipocytes/metabolism ; Adipose Tissue/metabolism ; Animals ; Carboxylesterase/genetics ; Carboxylesterase/metabolism ; Diabetes Mellitus, Type 2/genetics ; Diabetes Mellitus, Type 2/metabolism ; Diet, High-Fat ; Humans ; Mice
Chemical Substances	Carboxylesterase (EC 3.1.1.1) ; Ces1d protein, mouse (EC 3.1.1.1)
Language	English
Publishing date	2022-04-22
Publishing country	United States
Document type	Journal Article
ISSN	2575-1077
ISSN (online)	2575-1077
DOI	10.26508/lsa.202101209
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Article ; Online: Hepatic circadian and differentiation factors control liver susceptibility for fatty liver disease and tumorigenesis.

Fekry, Baharan / Ribas-Latre, Aleix / Drunen, Rachel Van / Santos, Rafael Bravo / Shivshankar, Samay / Dai, Yulin / Zhao, Zhongming / Yoo, Seung-Hee / Chen, Zheng / Sun, Kai / Sladek, Frances M / Younes, Mamoun / Eckel-Mahan, Kristin

FASEB journal : official publication of the Federation of American Societies for Experimental Biology

2022 Volume 36, Issue 9, Page(s) e22482

Abstract: Hepatocellular carcinoma (HCC) is a leading cause of cancer deaths, and the most common primary liver malignancy to present in the clinic. With the exception of liver transplant, treatment options for advanced HCC are limited, but improved tumor ... ...

Abstract	Hepatocellular carcinoma (HCC) is a leading cause of cancer deaths, and the most common primary liver malignancy to present in the clinic. With the exception of liver transplant, treatment options for advanced HCC are limited, but improved tumor stratification could open the door to new treatment options. Previously, we demonstrated that the circadian regulator Aryl Hydrocarbon-Like Receptor Like 1 (ARNTL, or Bmal1) and the liver-enriched nuclear factor 4 alpha (HNF4α) are robustly co-expressed in healthy liver but incompatible in the context of HCC. Faulty circadian expression of HNF4α- either by isoform switching, or loss of expression- results in an increased risk for HCC, while BMAL1 gain-of-function in HNF4α-positive HCC results in apoptosis and tumor regression. We hypothesize that the transcriptional programs of HNF4α and BMAL1 are antagonistic in liver disease and HCC. Here, we study this antagonism by generating a mouse model with inducible loss of hepatic HNF4α and BMAL1 expression. The results reveal that simultaneous loss of HNF4α and BMAL1 is protective against fatty liver and HCC in carcinogen-induced liver injury and in the "STAM" model of liver disease. Furthermore, our results suggest that targeting Bmal1 expression in the absence of HNF4α inhibits HCC growth and progression. Specifically, pharmacological suppression of Bmal1 in HNF4α-deficient, BMAL1-positive HCC with REV-ERB agonist SR9009 impairs tumor cell proliferation and migration in a REV-ERB-dependent manner, while having no effect on healthy hepatocytes. Collectively, our results suggest that stratification of HCC based on HNF4α and BMAL1 expression may provide a new perspective on HCC properties and potential targeted therapeutics.
MeSH term(s)	ARNTL Transcription Factors/genetics ; ARNTL Transcription Factors/metabolism ; Animals ; Carcinogenesis/genetics ; Carcinogenesis/pathology ; Carcinoma, Hepatocellular/metabolism ; Cell Transformation, Neoplastic/pathology ; Liver/metabolism ; Liver Neoplasms/metabolism ; Mice
Chemical Substances	ARNTL Transcription Factors
Language	English
Publishing date	2022-08-09
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	639186-2
ISSN	1530-6860 ; 0892-6638
ISSN (online)	1530-6860
ISSN	0892-6638
DOI	10.1096/fj.202101398R
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