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Jefcoate CR, Larsen MC, Song YS, Maguire M, Sheibani N. Defined Diets Link Iron and α-Linolenic Acid to Cyp1b1 Regulation of Neonatal Liver Development Through Srebp Forms and LncRNA H19. Int J Mol Sci 2025; 26:2011. [PMID: 40076634 PMCID: PMC11901102 DOI: 10.3390/ijms26052011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2024] [Revised: 01/10/2025] [Accepted: 01/15/2025] [Indexed: 03/14/2025] Open
Abstract
Cyp1b1 substantially affects hepatic vascular and stellate cells (HSC) with linkage to liver fibrosis. Despite minimal hepatocyte expression, Cyp1b1 deletion substantially impacts liver gene expression at birth and weaning. The appreciable Cyp1b1 expression in surrounding embryo mesenchyme, during early organogenesis, provides a likely source for Cyp1b1. Here defined breeder diets established major interconnected effects on neonatal liver of α-linolenic acid (ALA), vitamin A deficiency (VAD) and suboptimal iron fed mice. At birth Cyp1b1 deletion and VAD each activated perinatal HSC, while suppressing iron control by hepcidin. Cyp1b1 deletion also advanced the expression of diverse genes linked to iron regulation. Postnatal stimulations of Srebp-regulated genes in the fatty acid and cholesterol biosynthesis pathways were suppressed by Cyp1b1-deficiency. LncRNA H19 and the neutrophil alarmin S100a9 expression increased due to slower postnatal decline with Cyp1b1 deficiency. VAD reversed each of Cyp1b1 effect, probably due to enhanced HSC release of Apo-Rbp4. At birth, Cyp1b1 deletion enhanced H19 participation. Notably, a suppressor (Cnot3) decreased while an activity partner (Ezh2/H3K methylation) increased H19 expression. ALA elevated hepcidin mRNA and countered the inhibitory effects of Cyp1b1 deletion on hepcidin expression. Oxylipin metabolites of ALA from highly expressed hepatic Cyps are potential mediators. Cyp expression patterns demonstrated female dimorphism for neonatal liver. Mothers followed one of three fetal growth support programs probably linked to maturity at conception.
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Affiliation(s)
- Colin R. Jefcoate
- Department of Cell and Regenerative Biology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA; (M.C.L.); (M.M.)
| | - Michele C. Larsen
- Department of Cell and Regenerative Biology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA; (M.C.L.); (M.M.)
| | - Yong-Seok Song
- Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA;
| | - Meghan Maguire
- Department of Cell and Regenerative Biology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA; (M.C.L.); (M.M.)
| | - Nader Sheibani
- Department of Cell and Regenerative Biology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA; (M.C.L.); (M.M.)
- Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA;
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Kato-Suzuki M, Okamatsu-Ogura Y, Inanami O, Kimura K. Time-dependent changes in retinoids content in liver and adipose tissue after feeding of a vitamin A-deficient diet to mice. Exp Anim 2024; 73:302-309. [PMID: 38382988 PMCID: PMC11254491 DOI: 10.1538/expanim.23-0123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Accepted: 02/14/2024] [Indexed: 02/23/2024] Open
Abstract
Vitamin A is an important nutrient for multiple physiological functions. To elucidate the role of vitamin A in vivo, vitamin A-deficient diets have been often used in mice to establish a vitamin A-deficiency model. However, the information on the appropriate feeding periods and time course of changes in vitamin A content in organs after the start of vitamin A-deficient diet feeding is lacking. This study aimed to assess the retinoids levels in liver and white adipose tissue in mice fed a vitamin A-deficient diet for ≤8 weeks. High-performance liquid chromatography was used to measure the retinoids levels in liver and white adipose tissue every 2 weeks for ≤8 weeks. Vitamin A-deficient diet feeding significantly decreased retinol in the liver over 6 weeks, but retinyl palmitate, a main storage form of vitamin A, was not changed over 8 weeks. The plasma retinol level remained constant throughout the experiment. In white adipose tissue, retinyl palmitate gradually decreased over 8 weeks. These results indicate that vitamin A-deficient diet feeding longer than 6 weeks reduced retinol in liver and retinyl palmitate in white adipose tissue over 8 weeks, although it is not enough for the induction of a whole-body vitamin A deficiency.
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Affiliation(s)
- Mira Kato-Suzuki
- Laboratory of Biochemistry, Faculty of Veterinary Medicine, Hokkaido University, Kita 18, Nishi 9, Kita-ku, Sapporo, Hokkaido 060-0818, Japan
| | - Yuko Okamatsu-Ogura
- Laboratory of Biochemistry, Faculty of Veterinary Medicine, Hokkaido University, Kita 18, Nishi 9, Kita-ku, Sapporo, Hokkaido 060-0818, Japan
| | - Osamu Inanami
- Laboratory of Radiation Biology, Faculty of Veterinary Medicine, Hokkaido University, Kita 18, Nishi 9, Kita-ku, Sapporo, Hokkaido 060-0818, Japan
| | - Kazuhiro Kimura
- Laboratory of Biochemistry, Faculty of Veterinary Medicine, Hokkaido University, Kita 18, Nishi 9, Kita-ku, Sapporo, Hokkaido 060-0818, Japan
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FOSL2 deficiency delays nonalcoholic steatohepatitis progression by regulating LY6D-mediated NLRP3 activation. Hum Cell 2022; 35:1752-1765. [PMID: 35930135 DOI: 10.1007/s13577-022-00760-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Accepted: 07/24/2022] [Indexed: 12/27/2022]
Abstract
Lymphocyte antigen 6 family member D (LY6D) was enhanced specifically in senescent cells, while its effects on pyroptosis, a programmed cell death, remains unknown. The goal of this study was to assess the role of LY6D in the mediation of pyroptosis during nonalcoholic steatohepatitis (NASH). After screening out LY6D as a specific liver fibrosis-associated gene using the GSE55747 dataset from the GEO database, we established a NASH mouse model using methionine and choline deficient-diet feeding and an in vitro model using lipopolysaccharide (LPS)-treated hepatocytes. LY6D was overexpressed in NASH livers as well as in LPS-treated hepatocytes. Silencing of LY6D inhibited NASH-associated hepatocyte pyroptosis. With the aid of bioinformatics analysis, promoter-luciferase reporter and ChIP-qPCR assays, we identified FOSL2 as an upstream transcription factor of LY6D. FOSL2, which was highly expressed in NASH, promoted LY6D transcription by binding to the promoter of LY6D. Depletion of FOSL2 significantly inhibited NASH-associated hepatocyte pyroptosis, which was significantly reversed after overexpression of LY6D. Moreover, the promotion of hepatocyte pyroptosis by the FOSL2/LY6D axis was significantly attenuated by specific inhibition of NLRP3. These findings suggesting that FOSL2/LY6D axis may be a key molecular axis and a potential target for NASH therapeutics.
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Ilieva M, Dao J, Miller HE, Madsen JH, Bishop AJR, Kauppinen S, Uchida S. Systematic Analysis of Long Non-Coding RNA Genes in Nonalcoholic Fatty Liver Disease. Noncoding RNA 2022; 8:ncrna8040056. [PMID: 35893239 PMCID: PMC9332188 DOI: 10.3390/ncrna8040056] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Revised: 07/18/2022] [Accepted: 07/19/2022] [Indexed: 12/04/2022] Open
Abstract
The largest solid organ in humans, the liver, performs a variety of functions to sustain life. When damaged, cells in the liver can regenerate themselves to maintain normal liver physiology. However, some damage is beyond repair, which necessitates liver transplantation. Increasing rates of obesity, Western diets (i.e., rich in processed carbohydrates and saturated fats), and cardiometabolic diseases are interlinked to liver diseases, including non-alcoholic fatty liver disease (NAFLD), which is a collective term to describe the excess accumulation of fat in the liver of people who drink little to no alcohol. Alarmingly, the prevalence of NAFLD extends to 25% of the world population, which calls for the urgent need to understand the disease mechanism of NAFLD. Here, we performed secondary analyses of published RNA sequencing (RNA-seq) data of NAFLD patients compared to healthy and obese individuals to identify long non-coding RNAs (lncRNAs) that may underly the disease mechanism of NAFLD. Similar to protein-coding genes, many lncRNAs are dysregulated in NAFLD patients compared to healthy and obese individuals, suggesting that understanding the functions of dysregulated lncRNAs may shed light on the pathology of NAFLD. To demonstrate the functional importance of lncRNAs in the liver, loss-of-function experiments were performed for one NAFLD-related lncRNA, LINC01639, which showed that it is involved in the regulation of genes related to apoptosis, TNF/TGF, cytokine signaling, and growth factors as well as genes upregulated in NAFLD. Since there is no lncRNA database focused on the liver, especially NAFLD, we built a web database, LiverDB, to further facilitate functional and mechanistic studies of hepatic lncRNAs.
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Affiliation(s)
- Mirolyuba Ilieva
- Center for RNA Medicine, Department of Clinical Medicine, Aalborg University, DK-2450 Copenhagen SV, Denmark; (J.H.M.); (S.K.)
- Correspondence: (M.I.); (S.U.)
| | - James Dao
- Bioinformatics Research Network, Atlanta, GA 30317, USA; (J.D.); (H.E.M.)
| | - Henry E. Miller
- Bioinformatics Research Network, Atlanta, GA 30317, USA; (J.D.); (H.E.M.)
- Department of Cell Systems and Anatomy, UT Health San Antonio, San Antonio, TX 78229, USA;
- Greehey Children’s Cancer Research Institute, UT Health San Antonio, San Antonio, TX 78229, USA
| | - Jens Hedelund Madsen
- Center for RNA Medicine, Department of Clinical Medicine, Aalborg University, DK-2450 Copenhagen SV, Denmark; (J.H.M.); (S.K.)
| | - Alexander J. R. Bishop
- Department of Cell Systems and Anatomy, UT Health San Antonio, San Antonio, TX 78229, USA;
- Greehey Children’s Cancer Research Institute, UT Health San Antonio, San Antonio, TX 78229, USA
- May’s Cancer Center, UT Health San Antonio, San Antonio, TX 78229, USA
| | - Sakari Kauppinen
- Center for RNA Medicine, Department of Clinical Medicine, Aalborg University, DK-2450 Copenhagen SV, Denmark; (J.H.M.); (S.K.)
| | - Shizuka Uchida
- Center for RNA Medicine, Department of Clinical Medicine, Aalborg University, DK-2450 Copenhagen SV, Denmark; (J.H.M.); (S.K.)
- Bioinformatics Research Network, Atlanta, GA 30317, USA; (J.D.); (H.E.M.)
- Correspondence: (M.I.); (S.U.)
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Lei Z, Liu W, Nie Y, Yang Y, Chen G, Huang L, Wu H, Lei Y, Chen L, Hu Q, Rong H, Yu S, Song Q, Tong F, Guo J. EpCAM Is Essential to Maintaining the Immune Homeostasis of Intestines via Keeping the Expression of pIgR in the Intestinal Epithelium of Mice. Front Immunol 2022; 13:843378. [PMID: 35493520 PMCID: PMC9043958 DOI: 10.3389/fimmu.2022.843378] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2021] [Accepted: 03/22/2022] [Indexed: 11/30/2022] Open
Abstract
EpCAM deficiency causes congenital tufting enteropathy (CTE) which is considered as one kinds of very early onset inflammatory bowel disease (IBD). However, functions of EpCAM on regulating the immunity of intestines are still unclear. To study the mechanism of EpCAM on maintaining the intestinal immune homeostasis, the intestines of WT and EpCAM-/- mice at E18.5, P0 and P3 stages were collected for morphological, histological and gene expression tests. Serious inflammation was detected in the small intestines of P3 EpCAM-/- mice. Compared to WT mice, genes related to inflammatory factors and immunity cells, including TNFα, IL-1β, IL-6, IL-8rb, MIP2, MCP1, Ly6d and Ly6g, were all significantly upregulated and the expression of intestinal abundance matrix metalloproteinases (MMPs) was also significantly increased in the intestines of EpCAM-/- mice at E18.5, P0 and P3 stages. Signals of p38, ERK1/2 and JNK were hyper-activated in the intestines of EpCAM-/- mice. The expression of pIgR was significantly decreased and the expression and activation of transcriptional factors which promote the expression of pIgR were also reduced in the intestines of EpCAM-/- mice compared to WT controls. In conclusion, EpCAM could maintain the immune homeostasis of intestines via keeping the expression of pIgR in the intestinal epithelium.
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Affiliation(s)
- Zili Lei
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangdong Pharmaceutical University, Guangzhou, China
- *Correspondence: Zili Lei, ; Jiao Guo,
| | - Wanwan Liu
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangdong Pharmaceutical University, Guangzhou, China
| | - Ya Nie
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangdong Pharmaceutical University, Guangzhou, China
- School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou Higher Education Mega Center, Guangzhou, China
| | - Yanhong Yang
- The First Affiliated Hospital, School of Clinical Medicine, Guangdong Pharmaceutical University, Guangzhou, China
| | - Guibin Chen
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangdong Pharmaceutical University, Guangzhou, China
| | - Li Huang
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangdong Pharmaceutical University, Guangzhou, China
- School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou Higher Education Mega Center, Guangzhou, China
| | - Huijuan Wu
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangdong Pharmaceutical University, Guangzhou, China
- School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou Higher Education Mega Center, Guangzhou, China
| | - Yuting Lei
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangdong Pharmaceutical University, Guangzhou, China
| | - Lei Chen
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangdong Pharmaceutical University, Guangzhou, China
| | - Qing Hu
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangdong Pharmaceutical University, Guangzhou, China
| | - Hedong Rong
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangdong Pharmaceutical University, Guangzhou, China
- School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou Higher Education Mega Center, Guangzhou, China
| | - Siping Yu
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangdong Pharmaceutical University, Guangzhou, China
- School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou Higher Education Mega Center, Guangzhou, China
| | - Qi Song
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangdong Pharmaceutical University, Guangzhou, China
| | - Fengxue Tong
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangdong Pharmaceutical University, Guangzhou, China
| | - Jiao Guo
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangdong Pharmaceutical University, Guangzhou, China
- *Correspondence: Zili Lei, ; Jiao Guo,
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Yu L, Wang Y, Yu D, Zhang S, Zheng F, Ding N, Zhu L, Zhu Q, Sun W, Li S, Zhang G, Chen L, Liu Y, Yang L, Feng J. Association between Serum Vitamin A, Blood Lipid Level and Dyslipidemia among Chinese Children and Adolescents. Nutrients 2022; 14:nu14071444. [PMID: 35406055 PMCID: PMC9002720 DOI: 10.3390/nu14071444] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 03/20/2022] [Accepted: 03/28/2022] [Indexed: 01/11/2023] Open
Abstract
Background: To study the relationship between serum vitamin A (VA) level and blood lipid profiles in children and adolescents aged 6−18 years, as well as the effect of VA on dyslipidemia. Methods: The project adopted a multistage stratified cluster sampling method. The Food Frequency Questionnaire (FFQ) was used to obtain dietary factors data. Blood samples of subjects were taken via venipuncture. Generalized linear models were used to explore the correlation be-tween VA and biochemical indicators, as well as stratified and inter-actions analysis to explore the influence of confounders on these relationships. Generalized linear models were constructed to explore the association between VA and blood lipids. Restricted cubic splines were used to characterize dose−response associations between serum VA and dyslipidemia based on logistic regression. Results: Serum VA was positively correlated with TC, TG and HDL-C (p < 0.05), but these associations were influenced by age (p < 0.05). The adjusted odds ratio (OR) values of VA for hypercho lesterolemia, hypertriglyceridemia, mixed hyperlipidemia and low high-density lipoprotein cholesterolemia were 3.283, 3.239, 5.219 and 0.346, respectively (p < 0.01). Meanwhile, significant age interactions affected the relationship between VA and TC, as well as TG and LDL-C (p < 0.01). Conclusion: Serum VA was positively correlated with blood lipids, but these associations were influenced by age. VA was a risk factor for dyslipidemias, such as hypercholesterolemia, hypertriglyceridemia and mixed hyperlipidemia, but was a protective factor for low high-density lipoprotein cholesterolemia.
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Affiliation(s)
- Lianlong Yu
- Shandong Center for Disease Control and Prevention, Jinan 250014, China; (L.Y.); (F.Z.); (W.S.); (S.L.); (G.Z.); (L.C.)
| | - Yongjun Wang
- Department of Clinical Nutrition, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan 250014, China;
| | - Dongmei Yu
- National Institute for Nutrition and Health, Chinese Center for Disease Control and Prevention, Beijing 100050, China;
| | - Shixiu Zhang
- Department of Nutrition and Food Hygiene, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan 250012, China;
| | - Fengjia Zheng
- Shandong Center for Disease Control and Prevention, Jinan 250014, China; (L.Y.); (F.Z.); (W.S.); (S.L.); (G.Z.); (L.C.)
| | - Ning Ding
- Department of Pediatrics, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, China;
| | - Lichao Zhu
- Department of Pediatric Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, China;
| | - Qianrang Zhu
- Jiangsu Provincial Center for Disease Control and Prevention, Nanjing 210009, China;
| | - Wenkui Sun
- Shandong Center for Disease Control and Prevention, Jinan 250014, China; (L.Y.); (F.Z.); (W.S.); (S.L.); (G.Z.); (L.C.)
| | - Suyun Li
- Shandong Center for Disease Control and Prevention, Jinan 250014, China; (L.Y.); (F.Z.); (W.S.); (S.L.); (G.Z.); (L.C.)
| | - Gaohui Zhang
- Shandong Center for Disease Control and Prevention, Jinan 250014, China; (L.Y.); (F.Z.); (W.S.); (S.L.); (G.Z.); (L.C.)
| | - Liangxia Chen
- Shandong Center for Disease Control and Prevention, Jinan 250014, China; (L.Y.); (F.Z.); (W.S.); (S.L.); (G.Z.); (L.C.)
| | - Yiya Liu
- Guizhou Center for Disease Control and Prevention, Guiyang 550001, China;
| | - Li Yang
- Jinan Center for Disease Control and Prevention, Jinan 250021, China
- Correspondence: (L.Y.); (J.F.); Tel.: +86-18615422180 (L.Y.); +86-0531-82166927 (J.F.)
| | - Jian Feng
- Department of Clinical Nutrition, Qilu Hospital of Shandong University, Jinan 250012, China
- Correspondence: (L.Y.); (J.F.); Tel.: +86-18615422180 (L.Y.); +86-0531-82166927 (J.F.)
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Ho AMC, Winham SJ, McCauley BM, Kundakovic M, Robertson KD, Sun Z, Ordog T, Webb LM, Frye MA, Veldic M. Plasma Cell-Free DNA Methylomics of Bipolar Disorder With and Without Rapid Cycling. Front Neurosci 2021; 15:774037. [PMID: 34916903 PMCID: PMC8669968 DOI: 10.3389/fnins.2021.774037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Accepted: 11/01/2021] [Indexed: 11/21/2022] Open
Abstract
Rapid cycling (RC) burdens bipolar disorder (BD) patients further by causing more severe disability and increased suicidality. Because diagnosing RC can be challenging, RC patients are at risk of rapid decline due to delayed suitable treatment. Here, we aimed to identify the differences in the circulating cell-free DNA (cfDNA) methylome between BD patients with and without RC. The cfDNA methylome could potentially be developed as a diagnostic test for BD RC. We extracted cfDNA from plasma samples of BD1 patients (46 RC and 47 non-RC). cfDNA methylation levels were measured by 850K Infinium MethylationEPIC array. Principal component analysis (PCA) was conducted to assess global differences in methylome. cfDNA methylation levels were compared between RC groups using a linear model adjusted for age and sex. PCA suggested differences in methylation profiles between RC groups (p = 0.039) although no significant differentially methylated probes (DMPs; q > 0.15) were found. The top four CpG sites which differed between groups at p < 1E-05 were located in CGGPB1, PEX10, NR0B2, and TP53I11. Gene set enrichment analysis (GSEA) on top DMPs (p < 0.05) showed significant enrichment of gene sets related to nervous system tissues, such as neurons, synapse, and glutamate neurotransmission. Other top notable gene sets were related to parathyroid regulation and calcium signaling. To conclude, our study demonstrated the feasibility of utilizing a microarray method to identify circulating cfDNA methylation sites associated with BD RC and found the top differentially methylated CpG sites were mostly related to the nervous system and the parathyroid.
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Affiliation(s)
- Ada Man-Choi Ho
- Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, United States
| | - Stacey J Winham
- Department of Health Science Research, Mayo Clinic, Rochester, MN, United States
| | - Bryan M McCauley
- Department of Health Science Research, Mayo Clinic, Rochester, MN, United States
| | - Marija Kundakovic
- Department of Biological Sciences, Fordham University, New York, NY, United States
| | - Keith D Robertson
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, United States
| | - Zhifu Sun
- Department of Health Science Research, Mayo Clinic, Rochester, MN, United States
| | - Tamas Ordog
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, United States
| | - Lauren M Webb
- Mayo Clinic Alix School of Medicine, Rochester, MN, United States
| | - Mark A Frye
- Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, United States
| | - Marin Veldic
- Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, United States
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Christians A, Weiss AC, Martens H, Klopf MG, Hennies I, Haffner D, Kispert A, Weber RG. Inflammation-like changes in the urothelium of Lifr-deficient mice and LIFR-haploinsufficient humans with urinary tract anomalies. Hum Mol Genet 2021; 29:1192-1204. [PMID: 32179912 DOI: 10.1093/hmg/ddaa048] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Revised: 03/10/2020] [Accepted: 03/11/2020] [Indexed: 01/16/2023] Open
Abstract
Congenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause of end-stage kidney disease in children. While the genetic aberrations underlying CAKUT pathogenesis are increasingly being elucidated, their consequences on a cellular and molecular level commonly remain unclear. Recently, we reported rare heterozygous deleterious LIFR variants in 3.3% of CAKUT patients, including a novel de novo frameshift variant, identified by whole-exome sequencing, in a patient with severe bilateral CAKUT. We also demonstrated CAKUT phenotypes in Lifr-/- and Lifr+/- mice, including a narrowed ureteric lumen due to muscular hypertrophy and a thickened urothelium. Here, we show that both in the ureter and bladder of Lifr-/- and Lifr+/- embryos, differentiation of the three urothelial cell types (basal, intermediate and superficial cells) occurs normally but that the turnover of superficial cells is elevated due to increased proliferation, enhanced differentiation from their progenitor cells (intermediate cells) and, importantly, shedding into the ureteric lumen. Microarray-based analysis of genome-wide transcriptional changes in Lifr-/- versus Lifr+/+ ureters identified gene networks associated with an antimicrobial inflammatory response. Finally, in a reverse phenotyping effort, significantly more superficial cells were detected in the urine of CAKUT patients with versus without LIFR variants indicating conserved LIFR-dependent urinary tract changes in the murine and human context. Our data suggest that LIFR signaling is required in the epithelium of the urinary tract to suppress an antimicrobial response under homeostatic conditions and that genetically induced inflammation-like changes underlie CAKUT pathogenesis in Lifr deficiency and LIFR haploinsufficiency.
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Affiliation(s)
- Anne Christians
- Department of Human Genetics, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
| | - Anna-Carina Weiss
- Institute of Molecular Biology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
| | - Helge Martens
- Department of Human Genetics, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
| | - Maximilian Georg Klopf
- Institute of Molecular Biology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
| | - Imke Hennies
- Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
| | - Dieter Haffner
- Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
| | - Andreas Kispert
- Institute of Molecular Biology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
| | - Ruthild G Weber
- Department of Human Genetics, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
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9
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RNAseq studies reveal distinct transcriptional response to vitamin A deficiency in small intestine versus colon, uncovering novel vitamin A-regulated genes. J Nutr Biochem 2021; 98:108814. [PMID: 34242724 PMCID: PMC8908335 DOI: 10.1016/j.jnutbio.2021.108814] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2020] [Revised: 05/09/2021] [Accepted: 06/23/2021] [Indexed: 12/04/2022]
Abstract
Vitamin A (VA) deficiency remains prevalent in resource limited areas. Using Citrobacter rodentium infection in mice as a model for diarrheal diseases, previous reports showed reduced pathogen clearance and survival due to vitamin A deficient (VAD) status. To characterize the impact of preexisting VA deficiency on gene expression patterns in the intestines, and to discover novel target genes in VA-related biological pathways, VA deficiency in mice were induced by diet. Total mRNAs were extracted from small intestine (SI) and colon, and sequenced. Differentially Expressed Gene (DEG), Gene Ontology (GO) enrichment, and co-expression network analyses were performed. DEGs compared between VAS and VAD groups detected 49 SI and 94 colon genes. By GO information, SI DEGs were significantly enriched in categories relevant to retinoid metabolic process, molecule binding, and immune function. Three co-expression modules showed significant correlation with VA status in SI; these modules contained four known retinoic acid targets. In addition, other SI genes of interest (e.g., Mbl2, Cxcl14, and Nr0b2) in these modules were suggested as new candidate genes regulated by VA. Furthermore, our analysis showed that markers of two cell types in SI, mast cells and Tuft cells, were significantly altered by VA status. In colon, “cell division” was the only enriched category and was negatively associated with VA. Thus, these data suggested that SI and colon have distinct networks under the regulation of dietary VA, and that preexisting VA deficiency could have a significant impact on the host response to a variety of disease conditions.
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Yang FC, Xu F, Wang TN, Chen GX. Roles of vitamin A in the regulation of fatty acid synthesis. World J Clin Cases 2021; 9:4506-4519. [PMID: 34222419 PMCID: PMC8223857 DOI: 10.12998/wjcc.v9.i18.4506] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2021] [Revised: 03/25/2021] [Accepted: 04/21/2021] [Indexed: 02/06/2023] Open
Abstract
Dietary macronutrients and micronutrients play important roles in human health. On the other hand, the excessive energy derived from food is stored in the form of triacylglycerol. A variety of dietary and hormonal factors affect this process through the regulation of the activities and expression levels of those key player enzymes involved in fatty acid biosynthesis such as acetyl-CoA carboxylase, fatty acid synthase, fatty acid elongases, and desaturases. As a micronutrient, vitamin A is essential for the health of humans. Recently, vitamin A has been shown to play a role in the regulation of glucose and lipid metabolism. This review summarizes recent research progresses about the roles of vitamin A in fatty acid synthesis. It focuses on the effects of vitamin A on the activities and expression levels of mRNA and proteins of key enzymes for fatty acid synthesis in vitro and in vivo. It appears that vitamin A status and its signaling pathway regulate the expression levels of enzymes involved in fatty acid synthesis. Future research directions are also discussed.
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Affiliation(s)
- Fu-Chen Yang
- Food College, Jiangsu Food and Pharmaceutical College, Huaian 223003, Jiangsu Province, China
| | - Feng Xu
- Department of Urology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Tian-Nan Wang
- Department of Nutrition, The University of Tennessee, Knoxville, TN 37909, United States
| | - Guo-Xun Chen
- Department of Nutrition, The University of Tennessee, Knoxville, TN 37909, United States
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Maguire M, Larsen MC, Vezina CM, Quadro L, Kim YK, Tanumihardjo SA, Jefcoate CR. Cyp1b1 directs Srebp-mediated cholesterol and retinoid synthesis in perinatal liver; Association with retinoic acid activity during fetal development. PLoS One 2020; 15:e0228436. [PMID: 32027669 PMCID: PMC7004353 DOI: 10.1371/journal.pone.0228436] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2018] [Accepted: 01/16/2020] [Indexed: 12/13/2022] Open
Abstract
Background Cytochrome P450 1b1 (Cyp1b1) deletion and dietary retinol deficiency during pregnancy (GVAD) affect perinatal liver functions regulated by Srebp. Cyp1b1 is not expressed in perinatal liver but appears in the E9.5 embryo, close to sites of retinoic acid (RA) signaling. Hypothesis Parallel effects of Cyp1b1 and retinol on postnatal Srebp derive from effects in the developing liver or systemic signaling. Approach Cluster postnatal increases in hepatic genes in relation to effects of GVAD or Cyp1b1 deletion. Sort expression changes in relation to genes regulated by Srebp1 and Srebp2.Test these treatments on embryos at E9.5, examining changes at the site of liver initiation. Use in situ hybridization to resolve effects on mRNA distributions of Aldh1a2 and Cyp26a1 (RA homeostasis); Hoxb1 and Pax6 (RA targets). Assess mice lacking Lrat and Rbp4 (DKO mice) that severely limits retinol supply to embryos. Results At birth, GVAD and Cyp1b1 deletion stimulate gene markers of hepatic stellate cell (HSC) activation but also suppress Hamp. These treatments then selectively prevent the postnatal onset of genes that synthesize cholesterol (Hmgcr, Sqle) and fatty acids (Fasn, Scd1), but also direct cholesterol transport (Ldlr, Pcsk9, Stard4) and retinoid synthesis (Aldh1a1, Rdh11). Extensive support by Cyp1b1 is implicated, but with distinct GVAD interventions for Srebp1 and Srebp2. At E9.5, Cyp1b1 is expressed in the septum transversum mesenchyme (STM) with β-carotene oxygenase (Bco1) that generates retinaldehyde. STM provides progenitors for the HSC and supports liver expansion. GVAD and Cyp1b1-/- do not affect RA-dependent Hoxb1 and Pax6. In DKO embryos, RA-dependent Cyp26a1 is lost but Hoxb1 is sustained with Cyp1b1 at multiple sites. Conclusion Cyp1b1-/- suppresses genes supported by Srebp. GVAD effects distinguish Srebp1 and Srebp2 mediation. Srebp regulation overlaps appreciably in cholesterol and retinoid homeostasis. Bco1/Cyp1b1 partnership in the STM may contribute to this later liver regulation.
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Affiliation(s)
- Meghan Maguire
- Endocrinology and Reproductive Physiology Program, University of Wisconsin-Madison, Madison, WI
- Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison, WI
| | | | - Chad M. Vezina
- Department of Comparative Biosciences, University of Wisconsin-Madison, Madison, WI
| | - Loredana Quadro
- Department of Food Science and Rutgers Center for Lipid Research, Rutgers University, New Brunswick, New Jersey
| | - Youn-Kyung Kim
- Department of Food Science and Rutgers Center for Lipid Research, Rutgers University, New Brunswick, New Jersey
| | | | - Colin R. Jefcoate
- Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison, WI
- * E-mail:
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Jiang B, Lv Q, Wan W, Le L, Xu L, Hu K, Xiao P. Transcriptome analysis reveals the mechanism of the effect of flower tea Coreopsis tinctoria on hepatic insulin resistance. Food Funct 2019; 9:5607-5620. [PMID: 30370909 DOI: 10.1039/c8fo00965a] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Non-Camellia tea and herbal medicine help prevent the development of diabetes and other metabolic diseases. Previous studies revealed that Coreopsis tinctoria (CT) flower tea increases insulin sensitivity and, in some high-fat diet (HFD)-fed rats, even prevents hepatic metabolic disorders. However, the molecular mechanisms by which CT improves insulin resistance are not known. In this study, six-week-old rats were fed a normal diet (ND), an HFD or an HFD supplemented with CT for 8 weeks. Serum samples were collected, and the livers were extracted for RNA-seq gene expression analysis. Real-time PCR and western blotting further verified the RNA-seq results. In our results, dietary CT ameliorated HFD-induced hepatosteatosis, glucose intolerance, and insulin resistance. In the HFD group, 1667 differentially expressed genes (DEGs) were identified compared with the ND group. In the CT group, 327 DEGs were identified compared with the HFD group. Some of these DEGs were related to insulin signalling, hepatic lipogenesis and glucose homeostasis. This study suggested that insulin resistance with hyperinsulinaemia, and not insulin insufficiency, is an early problem in HFD-fed rats, and CT downregulates insulin secretion genes (e.g., Rasd1, Stxbp1 and Sfxn1). Hepatic gene and protein expression analyses indicated that the regulatory effects of CT on glucose and lipid homeostasis are likely mediated via the Akt/FoxO1 signalling pathway and are regulated by the transcription factors hairy and enhancer of split 1 (HES1) and small heterodimer partner (SHP). Our study provides transcriptomic evidence of the complex pathogenic mechanism involved in hepatic insulin resistance and proves that supplementation with CT improves insulin resistance at a global scale.
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Affiliation(s)
- Baoping Jiang
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100193, China.
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Maguire M, Larsen MC, Foong YH, Tanumihardjo S, Jefcoate CR. Cyp1b1 deletion and retinol deficiency coordinately suppress mouse liver lipogenic genes and hepcidin expression during post-natal development. Mol Cell Endocrinol 2017; 454:50-68. [PMID: 28583802 PMCID: PMC5985816 DOI: 10.1016/j.mce.2017.05.037] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2016] [Revised: 05/30/2017] [Accepted: 05/30/2017] [Indexed: 02/06/2023]
Abstract
UNLABELLED Cyp1b1 deletion and gestational vitamin A deficiency (GVAD) redirect adult liver gene expression. A matched sufficient pre- and post-natal diet, which has high carbohydrate and normal iron content (LF12), increased inflammatory gene expression markers in adult livers that were suppressed by GVAD and Cyp1b1 deletion. At birth on the LF12 diet, Cyp1b1 deletion and GVAD each suppress liver expression of the iron suppressor, hepcidin (Hepc), while increasing stellate cell activation markers and suppressing post-natal increases in lipogenesis. Hepc was less suppressed in Cyp1b1-/- pups with a standard breeder diet, but was restored by iron supplementation of the LF12 diet. CONCLUSIONS The LF12 diet delivered low post-natal iron and attenuated Hepc. Hepc decreases in Cyp1b1-/- and GVAD mice resulted in stellate activation and lipogenesis suppression. Endothelial BMP6, a Hepc stimulant, is a potential coordinator and Cyp1b1 target. These neonatal changes in Cyp1b1-/- mice link to diminished adult obesity and liver inflammation.
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Affiliation(s)
- Meghan Maguire
- Endocrinology and Reproductive Physiology Program, University of Wisconsin-Madison, Madison, WI 53705, United States; Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison, WI 53705, United States
| | - Michele Campaigne Larsen
- Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison, WI 53705, United States
| | - Yee Hoon Foong
- Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison, WI 53705, United States
| | - Sherry Tanumihardjo
- Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, WI 53705, United States
| | - Colin R Jefcoate
- Endocrinology and Reproductive Physiology Program, University of Wisconsin-Madison, Madison, WI 53705, United States; Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison, WI 53705, United States.
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