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Todorović D, Stojanović M, Mutavdžin Krneta S, Jakovljević Uzelac J, Gopčević K, Medić A, Labudović Borović M, Stanković S, Djuric DM. Effects of four-week lasting aerobic treadmill training on hepatic injury biomarkers, oxidative stress parameters, metabolic enzymes activities and histological characteristics in liver tissue of hyperhomocysteinemic rats. Mol Cell Biochem 2025; 480:2511-2524. [PMID: 39384708 DOI: 10.1007/s11010-024-05133-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Accepted: 10/04/2024] [Indexed: 10/11/2024]
Abstract
Disruptions in homocysteine (Hcy) metabolism may increase the liver's susceptibility to developing conditions such as alcoholic liver disease, viral hepatitis, hepatocellular carcinoma (HCC), and cirrhosis. The aim of this study was to examine effects of aerobic treadmill training on hepatic injury biomarkers in sera, oxidative stress parameters, the activity of metabolic enzymes, and histological characteristics in the liver tissue of rats with experimentally induced hyperhomocysteinemia. Male Wistar albino rats were divided into four groups (N = 10, per group): C-saline 0.2 mL/day sc. 2×/day for 14 days + saline 0.5 mL ip.1×/day for 28 days; H-homocysteine 0.45 µmol/g b.w. 2×/day for 14 days + saline 0.5 mL ip.1×/day for 28 days; CPA-saline 0.2 mL/day sc. 2×/day for 14 days + aerobic treadmill training for 28 days; and HPA-homocysteine 0.45 µmol/g b.w. 2×/day for 14 days + aerobic treadmill training for 28 days. The serum albumin concentration was decreased in both physically active (PA) groups compared to sedentary groups. Concentration of malondialdehyde in liver tissue homogenates was lower in both PA groups compared to the H group. The total lactate dehydrogenase and malate dehydrogenase activities were significantly elevated in the HPA group compared to the C and H groups. Activities of aminotransferases in sera samples, and activities of catalase and superoxide dismutase in liver tissue did not significantly differ between groups. No significant histological changes were found in liver tissue in groups. This study demonstrated that aerobic treadmill training can reduce lipid peroxidation in liver tissue under hyperhomocysteinemic conditions, providing a protective effect. However, hyperhomocysteinemia can alter energy metabolism during aerobic exercise, shifting it toward anaerobic pathways and leading to elevated lactate dehydrogenase activity in the liver. Given that conditions like hyperhomocysteinemia are associated with an increased risk of cardiovascular diseases and liver damage, understanding how exercise influences these dynamics could guide therapeutic approaches.
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Affiliation(s)
- Dušan Todorović
- Faculty of Medicine, Institute of Medical Physiology "Richard Burian", University of Belgrade, Belgrade, Serbia
| | - Marija Stojanović
- Faculty of Medicine, Institute of Medical Physiology "Richard Burian", University of Belgrade, Belgrade, Serbia
| | - Slavica Mutavdžin Krneta
- Faculty of Medicine, Institute of Medical Physiology "Richard Burian", University of Belgrade, Belgrade, Serbia
| | - Jovana Jakovljević Uzelac
- Faculty of Medicine, Institute of Medical Physiology "Richard Burian", University of Belgrade, Belgrade, Serbia
| | - Kristina Gopčević
- Faculty of Medicine, Institute of Chemistry in Medicine "Petar Matavulj", University of Belgrade, Belgrade, Serbia
| | - Ana Medić
- Faculty of Medicine, Institute of Chemistry in Medicine "Petar Matavulj", University of Belgrade, Belgrade, Serbia
| | - Milica Labudović Borović
- Faculty of Medicine, Institute of Histology and Embryology "Aleksandar Dj. Kostic", University of Belgrade, Belgrade, Serbia
| | - Sanja Stanković
- Center for Medical Biochemistry, University Clinical Center of Serbia, Belgrade, Serbia
- Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
| | - Dragan M Djuric
- Faculty of Medicine, Institute of Medical Physiology "Richard Burian", University of Belgrade, Belgrade, Serbia.
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Wang YW, Chu T, Wang XL, Fan YQ, Cao L, Chen YH, Zhu YW, Liu HX, Ji XY, Wu DD. The role of cystathionine β-synthase in cancer. Cell Signal 2024; 124:111406. [PMID: 39270916 DOI: 10.1016/j.cellsig.2024.111406] [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: 07/12/2024] [Revised: 08/28/2024] [Accepted: 09/09/2024] [Indexed: 09/15/2024]
Abstract
Cystathionine β-synthase (CBS) occupies a key position as the initiating and rate-limiting enzyme in the sulfur transfer pathway and plays a vital role in health and disease. CBS is responsible for regulating the metabolism of cysteine, the precursor of glutathione (GSH), an important antioxidant in the body. Additionally, CBS is one of the three enzymes that produce hydrogen sulfide (H2S) in mammals through a variety of mechanisms. The dysregulation of CBS expression in cancer cells affects H2S production through direct or indirect pathways, thereby influencing cancer growth and metastasis by inducing angiogenesis, facilitating proliferation, migration, and invasion, modulating cellular energy metabolism, promoting cell cycle progression, and inhibiting apoptosis. It is noteworthy that CBS expression exhibits complex changes in different cancer models. In this paper, we focus on the CBS synthesis and metabolism, tissue distribution, potential mechanisms influencing tumor growth, and relevant signaling pathways. We also discuss the impact of pharmacological CBS inhibitors and silencing CBS in preclinical cancer models, supporting their potential as targeted cancer therapies.
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Affiliation(s)
- Yan-Wen Wang
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, School of Stomatology, Henan University, Kaifeng, Henan 475004, China
| | - Ti Chu
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, School of Stomatology, Henan University, Kaifeng, Henan 475004, China
| | - Xue-Li Wang
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, School of Stomatology, Henan University, Kaifeng, Henan 475004, China
| | - Yong-Qi Fan
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, School of Stomatology, Henan University, Kaifeng, Henan 475004, China
| | - Lei Cao
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, School of Stomatology, Henan University, Kaifeng, Henan 475004, China
| | - Yu-Hang Chen
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, School of Stomatology, Henan University, Kaifeng, Henan 475004, China
| | - Yi-Wen Zhu
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, School of Stomatology, Henan University, Kaifeng, Henan 475004, China
| | - Hong-Xia Liu
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, School of Stomatology, Henan University, Kaifeng, Henan 475004, China; Department of Stomatology, Huaihe Hospital of Henan University, School of Stomatology, Henan University, Kaifeng, Henan 475004, China.
| | - Xin-Ying Ji
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, School of Stomatology, Henan University, Kaifeng, Henan 475004, China; Faculty of Basic Medical Subjects, Shu-Qing Medical College of Zhengzhou, Zhengzhou, Henan 450064, China.
| | - Dong-Dong Wu
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, School of Stomatology, Henan University, Kaifeng, Henan 475004, China; Department of Stomatology, Huaihe Hospital of Henan University, School of Stomatology, Henan University, Kaifeng, Henan 475004, China.
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Balci MC, Gedikbasi A, Dogan SA, Kahraman S, Tatoryan S, Neijmann ST, Karaca M, Atalar F, Gokcay G. Oxidative damage and mitochondrial dysfunction in cystathionine beta-synthase deficiency. Sci Rep 2024; 14:28815. [PMID: 39567721 PMCID: PMC11579338 DOI: 10.1038/s41598-024-80273-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Accepted: 11/18/2024] [Indexed: 11/22/2024] Open
Abstract
Cystathionine beta-synthase deficiency (CBSD) is the most prevalent inherited disorder of homocysteine metabolism in the transsulphuration pathway. Research have suggested oxidative stress and inflammation as candidate pathogenic mechanisms in CBSD. This study aims to evaluate mitochondrial dysfunction and oxidative stress biomarkers in cystathionine beta-synthase deficiency (CBSD) patients, which may aid in understanding the pathogenesis of CBSD and improving treatment. The study group comprised 23 patients with a diagnosis of CBSD and healthy controls. We analysed serum levels of NAD+ and NADH by fluorometric assay, FGF-21 and GDF-15 by ELISA, mitochondrial DAMPs by real time qRT-PCR, total homocysteine levels in plasma by enzymatic test and compared the results in CBSD group with healthy controls. In patient group, a positive correlation was found between the total homocysteine level and both GDF-15 and NAD+/NADH levels. Furthermore, there was a negative correlation between total homocysteine levels and both total NAD++NADH and NADH levels. The alterations in NAD+, FGF-21, GDF-15 levels, and NAD+/NADH ratio in patients suggest that oxidative damage coexists with mitochondrial dysfunction in CBSD. Assessment of oxidative damage and addition of anti-oxidant therapy together with mitochondrial support may have additional benefits in reducing long-term morbidity in CBSD patients.
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Affiliation(s)
- Mehmet Cihan Balci
- Division of Pediatric Nutrition and Metabolism, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Türkiye, Turkey.
- Istanbul Faculty of Medicine, Division of Nutrition and Metabolism, Children's Hospital, Turgut Ozal Millet Cd, Fatih, Istanbul, 34093, Türkiye, Turkey.
| | - Asuman Gedikbasi
- Department of Pediatric Basic Sciences, Institute of Child Health, Istanbul University, Istanbul, Türkiye, Turkey
| | - Sukru Anil Dogan
- Department of Molecular Biology and Genetics, Center for Life Sciences and Technologies, Bogazici University, Istanbul, Türkiye, Turkey
| | - Sevde Kahraman
- Department of Rare Diseases, Institute of Health Sciences, Istanbul University, Istanbul, Türkiye, Turkey
| | - Suzin Tatoryan
- Department of Rare Diseases, Institute of Child Health, Istanbul University, Istanbul, Türkiye, Turkey
| | - Sebnem Tekin Neijmann
- Department of Rare Diseases, Institute of Health Sciences, Istanbul University, Istanbul, Türkiye, Turkey
| | - Meryem Karaca
- Division of Pediatric Nutrition and Metabolism, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Türkiye, Turkey
| | - Fatmahan Atalar
- Department of Rare Diseases, Institute of Child Health, Istanbul University, Istanbul, Türkiye, Turkey
| | - Gulden Gokcay
- Division of Pediatric Nutrition and Metabolism, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Türkiye, Turkey
- Department of Rare Diseases, Institute of Health Sciences, Istanbul University, Istanbul, Türkiye, Turkey
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Zhu X, Cao Y, Chen S, Liu Q, Chai J, Wang W. Insufficient S-sulfhydration of serum and glucocorticoid-regulated kinase 1 participates in hyperhomocysteinemia-induced liver injury. Free Radic Biol Med 2024; 225:517-527. [PMID: 39427745 DOI: 10.1016/j.freeradbiomed.2024.10.294] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Revised: 10/01/2024] [Accepted: 10/17/2024] [Indexed: 10/22/2024]
Abstract
BACKGROUND & AIMS Previous studies have established that hyperhomocysteinemia (HHcy) significantly contributes to the development of non-alcoholic steatohepatitis (NASH). Conversely, hydrogen sulfide (H2S) has shown potential in mitigating NASH. Despite these findings, it remains uncertain whether H2S can serve as a therapeutic agent against HHcy-induced liver damage. METHODS Mice were fed a high-methionine diet to induce HHcy and HepG2 cells were exposed to homocysteine (Hcy). In both models, we assessed liver injury, H2S concentration, and autophagy levels. For rescue, sodium hydrosulfide (NaHS), an H2S donor, was used to test its potential in reversing hepatic pathological features induced by HHcy. RESULTS 1) Hcy accumulation led to liver damage and increased autophagy. This was linked to insufficient S-sulfhydration of serum and glucocorticoid-regulated kinase 1 (SGK1) at Cys244 and Cys282, a crucial autophagy regulator. The deficiency in S-sulfhydration was resulted from downregulation of cystathionine-γ-lyase (CSE) and subsequent H2S decrease, leading to SGK1 inactivation. 2) Administration of NaHS reduced the liver damage caused by high Hcy levels and restored H2S levels, promoting the S-sulfhydration and activation of SGK1. 3) Pharmacological inhibition of SGK1 induced autosis, a specific type of cell death caused by overactivation of autophagy. Conversely, a constitutively active mutant of SGK1 (SGK1S422D) significantly decreased autophagy and improved cell viability. CONCLUSIONS NaHS supplementation mitigates HHcy-induced liver injury by downregulating hepatic autophagy through the S-sulfhydration and activation of SGK1. This post-translational modification by H2S holds promise as a therapeutic approach for HHcy-induced liver injury.
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Affiliation(s)
- Xinyu Zhu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China
| | - Yan Cao
- Department of Basic Medical Sciences, Beijing Health Vocational College, Beijing, 101149, China
| | - Shuai Chen
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China
| | - Qinchi Liu
- School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China
| | - Jiayin Chai
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China
| | - Wen Wang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China; Beijing Key Laboratory for Metabolic Disorder-Related Cardiovascular Diseases, Beijing, 100069, China.
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Sun HJ, Lu QB, Zhu XX, Ni ZR, Su JB, Fu X, Chen G, Zheng GL, Nie XW, Bian JS. Pharmacology of Hydrogen Sulfide and Its Donors in Cardiometabolic Diseases. Pharmacol Rev 2024; 76:846-895. [PMID: 38866561 DOI: 10.1124/pharmrev.123.000928] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Revised: 04/13/2024] [Accepted: 06/10/2024] [Indexed: 06/14/2024] Open
Abstract
Cardiometabolic diseases (CMDs) are major contributors to global mortality, emphasizing the critical need for novel therapeutic interventions. Hydrogen sulfide (H2S) has garnered enormous attention as a significant gasotransmitter with various physiological, pathophysiological, and pharmacological impacts within mammalian cardiometabolic systems. In addition to its roles in attenuating oxidative stress and inflammatory response, burgeoning research emphasizes the significance of H2S in regulating proteins via persulfidation, a well known modification intricately associated with the pathogenesis of CMDs. This review seeks to investigate recent updates on the physiological actions of endogenous H2S and the pharmacological roles of various H2S donors in addressing diverse aspects of CMDs across cellular, animal, and clinical studies. Of note, advanced methodologies, including multiomics, intestinal microflora analysis, organoid, and single-cell sequencing techniques, are gaining traction due to their ability to offer comprehensive insights into biomedical research. These emerging approaches hold promise in characterizing the pharmacological roles of H2S in health and diseases. We will critically assess the current literature to clarify the roles of H2S in diseases while also delineating the opportunities and challenges they present in H2S-based pharmacotherapy for CMDs. SIGNIFICANCE STATEMENT: This comprehensive review covers recent developments in H2S biology and pharmacology in cardiometabolic diseases CMDs. Endogenous H2S and its donors show great promise for the management of CMDs by regulating numerous proteins and signaling pathways. The emergence of new technologies will considerably advance the pharmacological research and clinical translation of H2S.
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Affiliation(s)
- Hai-Jian Sun
- Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China (H.-J.S., X.-X.Z., Z.-R.N., J.-B.S., X.F., G.C., G.-L.Z.); Department of Endocrinology, Affiliated Hospital of Jiangnan University, Jiangnan University, Wuxi, Jiangsu, China (Q.-B.L.); Shenzhen Key Laboratory of Respiratory Diseases, Shenzhen People's Hospital, Shenzhen, Guangdong, China (X.-W.N.); and Department of Pharmacology, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong, China (J.-S.B.)
| | - Qing-Bo Lu
- Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China (H.-J.S., X.-X.Z., Z.-R.N., J.-B.S., X.F., G.C., G.-L.Z.); Department of Endocrinology, Affiliated Hospital of Jiangnan University, Jiangnan University, Wuxi, Jiangsu, China (Q.-B.L.); Shenzhen Key Laboratory of Respiratory Diseases, Shenzhen People's Hospital, Shenzhen, Guangdong, China (X.-W.N.); and Department of Pharmacology, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong, China (J.-S.B.)
| | - Xue-Xue Zhu
- Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China (H.-J.S., X.-X.Z., Z.-R.N., J.-B.S., X.F., G.C., G.-L.Z.); Department of Endocrinology, Affiliated Hospital of Jiangnan University, Jiangnan University, Wuxi, Jiangsu, China (Q.-B.L.); Shenzhen Key Laboratory of Respiratory Diseases, Shenzhen People's Hospital, Shenzhen, Guangdong, China (X.-W.N.); and Department of Pharmacology, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong, China (J.-S.B.)
| | - Zhang-Rong Ni
- Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China (H.-J.S., X.-X.Z., Z.-R.N., J.-B.S., X.F., G.C., G.-L.Z.); Department of Endocrinology, Affiliated Hospital of Jiangnan University, Jiangnan University, Wuxi, Jiangsu, China (Q.-B.L.); Shenzhen Key Laboratory of Respiratory Diseases, Shenzhen People's Hospital, Shenzhen, Guangdong, China (X.-W.N.); and Department of Pharmacology, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong, China (J.-S.B.)
| | - Jia-Bao Su
- Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China (H.-J.S., X.-X.Z., Z.-R.N., J.-B.S., X.F., G.C., G.-L.Z.); Department of Endocrinology, Affiliated Hospital of Jiangnan University, Jiangnan University, Wuxi, Jiangsu, China (Q.-B.L.); Shenzhen Key Laboratory of Respiratory Diseases, Shenzhen People's Hospital, Shenzhen, Guangdong, China (X.-W.N.); and Department of Pharmacology, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong, China (J.-S.B.)
| | - Xiao Fu
- Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China (H.-J.S., X.-X.Z., Z.-R.N., J.-B.S., X.F., G.C., G.-L.Z.); Department of Endocrinology, Affiliated Hospital of Jiangnan University, Jiangnan University, Wuxi, Jiangsu, China (Q.-B.L.); Shenzhen Key Laboratory of Respiratory Diseases, Shenzhen People's Hospital, Shenzhen, Guangdong, China (X.-W.N.); and Department of Pharmacology, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong, China (J.-S.B.)
| | - Guo Chen
- Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China (H.-J.S., X.-X.Z., Z.-R.N., J.-B.S., X.F., G.C., G.-L.Z.); Department of Endocrinology, Affiliated Hospital of Jiangnan University, Jiangnan University, Wuxi, Jiangsu, China (Q.-B.L.); Shenzhen Key Laboratory of Respiratory Diseases, Shenzhen People's Hospital, Shenzhen, Guangdong, China (X.-W.N.); and Department of Pharmacology, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong, China (J.-S.B.)
| | - Guan-Li Zheng
- Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China (H.-J.S., X.-X.Z., Z.-R.N., J.-B.S., X.F., G.C., G.-L.Z.); Department of Endocrinology, Affiliated Hospital of Jiangnan University, Jiangnan University, Wuxi, Jiangsu, China (Q.-B.L.); Shenzhen Key Laboratory of Respiratory Diseases, Shenzhen People's Hospital, Shenzhen, Guangdong, China (X.-W.N.); and Department of Pharmacology, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong, China (J.-S.B.)
| | - Xiao-Wei Nie
- Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China (H.-J.S., X.-X.Z., Z.-R.N., J.-B.S., X.F., G.C., G.-L.Z.); Department of Endocrinology, Affiliated Hospital of Jiangnan University, Jiangnan University, Wuxi, Jiangsu, China (Q.-B.L.); Shenzhen Key Laboratory of Respiratory Diseases, Shenzhen People's Hospital, Shenzhen, Guangdong, China (X.-W.N.); and Department of Pharmacology, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong, China (J.-S.B.)
| | - Jin-Song Bian
- Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China (H.-J.S., X.-X.Z., Z.-R.N., J.-B.S., X.F., G.C., G.-L.Z.); Department of Endocrinology, Affiliated Hospital of Jiangnan University, Jiangnan University, Wuxi, Jiangsu, China (Q.-B.L.); Shenzhen Key Laboratory of Respiratory Diseases, Shenzhen People's Hospital, Shenzhen, Guangdong, China (X.-W.N.); and Department of Pharmacology, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong, China (J.-S.B.)
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Yan H, Liu W, Xiang R, Li X, Hou S, Xu L, Wang L, Zhao D, Liu X, Wang G, Chi Y, Yang J. Ribosomal modification protein rimK-like family member A activates betaine-homocysteine S-methyltransferase 1 to ameliorate hepatic steatosis. Signal Transduct Target Ther 2024; 9:214. [PMID: 39117631 PMCID: PMC11310345 DOI: 10.1038/s41392-024-01914-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Revised: 06/14/2024] [Accepted: 07/04/2024] [Indexed: 08/10/2024] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a serious threat to public health, but its underlying mechanism remains poorly understood. In screening important genes using Gene Importance Calculator (GIC) we developed previously, ribosomal modification protein rimK-like family member A (RIMKLA) was predicted as one essential gene but its functions remained largely unknown. The current study determined the roles of RIMKLA in regulating glucose and lipid metabolism. RIMKLA expression was reduced in livers of human and mouse with NAFLD. Hepatic RIMKLA overexpression ameliorated steatosis and hyperglycemia in obese mice. Hepatocyte-specific RIMKLA knockout aggravated high-fat diet (HFD)-induced dysregulated glucose/lipid metabolism in mice. Mechanistically, RIMKLA is a new protein kinase that phosphorylates betaine-homocysteine S-methyltransferase 1 (BHMT1) at threonine 45 (Thr45) site. Upon phosphorylation at Thr45 and activation, BHMT1 eliminated homocysteine (Hcy) to inhibit the activity of transcription factor activator protein 1 (AP1) and its induction on fatty acid synthase (FASn) and cluster of differentiation 36 (CD36) gene transcriptions, concurrently repressing lipid synthesis and uptake in hepatocytes. Thr45 to alanine (T45A) mutation inactivated BHMT1 to abolish RIMKLA's repression on Hcy level, AP1 activity, FASn/CD36 expressions, and lipid deposition. BHMT1 overexpression rescued the dysregulated lipid metabolism in RIMKLA-deficient hepatocytes. In summary, RIMKLA is a novel protein kinase that phosphorylates BHMT1 at Thr45 to repress lipid synthesis and uptake. Under obese condition, inhibition of RIMKLA impairs BHMT1 activity to promote hepatic lipid deposition.
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Affiliation(s)
- Han Yan
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Center for Non-coding RNA Medicine, Peking University Health Science Center, Beijing, 100191, China
- Department of Endocrinology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310058, China
| | - Wenjun Liu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Center for Non-coding RNA Medicine, Peking University Health Science Center, Beijing, 100191, China
| | - Rui Xiang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Center for Non-coding RNA Medicine, Peking University Health Science Center, Beijing, 100191, China
| | - Xin Li
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Center for Non-coding RNA Medicine, Peking University Health Science Center, Beijing, 100191, China
| | - Song Hou
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Center for Non-coding RNA Medicine, Peking University Health Science Center, Beijing, 100191, China
| | - Luzheng Xu
- Medical and Health Analysis Center, Peking University, Beijing, 100191, China
| | - Lin Wang
- Department of Hepatobiliary Surgery, Xi-Jing Hospital, Fourth Military Medical University, Xi'an, 710032, China
| | - Dong Zhao
- Department of Endocrinology, Beijing Luhe Hospital, Capital Medical University, Beijing, 101100, China
| | - Xingkai Liu
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Centre, First Hospital of Jilin University, Changchun, 130061, China.
| | - Guoqing Wang
- Key Laboratory of Pathobiology Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, 130012, China.
| | - Yujing Chi
- Department of Central Laboratory and Institute of Clinical Molecular Biology, Department of Gastroenterology, Peking University People's Hospital, Beijing, 100044, China.
| | - Jichun Yang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Center for Non-coding RNA Medicine, Peking University Health Science Center, Beijing, 100191, China.
- Department of Cardiology, Peking University Third Hospital, Beijing, 100191, China.
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Zou Y, Yuan Y, Zhou Q, Yue Z, Liu J, Fan L, Xu H, Xin L. The Role of Methionine Restriction in Gastric Cancer: A Summary of Mechanisms and a Discussion on Tumor Heterogeneity. Biomolecules 2024; 14:161. [PMID: 38397398 PMCID: PMC10887009 DOI: 10.3390/biom14020161] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2023] [Revised: 01/18/2024] [Accepted: 01/24/2024] [Indexed: 02/25/2024] Open
Abstract
Gastric cancer is ranked as the fifth most prevalent cancer globally and has long been a topic of passionate discussion among numerous individuals. However, the incidence of gastric cancer in society has not decreased, but instead has shown a gradual increase in recent years. For more than a decade, the treatment effect of gastric cancer has not been significantly improved. This is attributed to the heterogeneity of cancer, which makes popular targeted therapies ineffective. Methionine is an essential amino acid, and many studies have shown that it is involved in the development of gastric cancer. Our study aimed to review the literature on methionine and gastric cancer, describing its mechanism of action to show that tumor heterogeneity in gastric cancer does not hinder the effectiveness of methionine-restricted therapies. This research also aimed to provide insight into the inhibition of gastric cancer through metabolic reprogramming with methionine-restricted therapies, thereby demonstrating their potential as adjuvant treatments for gastric cancer.
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Affiliation(s)
| | | | | | | | | | | | | | - Lin Xin
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, No. 1 Minde Road, Donghu District, Nanchang 330006, China; (Y.Z.); (Y.Y.); (Q.Z.); (Z.Y.); (J.L.); (L.F.); (H.X.)
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Youness RA, Habashy DA, Khater N, Elsayed K, Dawoud A, Hakim S, Nafea H, Bourquin C, Abdel-Kader RM, Gad MZ. Role of Hydrogen Sulfide in Oncological and Non-Oncological Disorders and Its Regulation by Non-Coding RNAs: A Comprehensive Review. Noncoding RNA 2024; 10:7. [PMID: 38250807 PMCID: PMC10801522 DOI: 10.3390/ncrna10010007] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2023] [Revised: 01/07/2024] [Accepted: 01/08/2024] [Indexed: 01/23/2024] Open
Abstract
Recently, myriad studies have defined the versatile abilities of gasotransmitters and their synthesizing enzymes to play a "Maestro" role in orchestrating several oncological and non-oncological circuits and, thus, nominated them as possible therapeutic targets. Although a significant amount of work has been conducted on the role of nitric oxide (NO) and carbon monoxide (CO) and their inter-relationship in the field of oncology, research about hydrogen sulfide (H2S) remains in its infancy. Recently, non-coding RNAs (ncRNAs) have been reported to play a dominating role in the regulation of the endogenous machinery system of H2S in several pathological contexts. A growing list of microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) are leading the way as upstream regulators for H2S biosynthesis in different mammalian cells during the development and progression of human diseases; therefore, their targeting can be of great therapeutic benefit. In the current review, the authors shed the light onto the biosynthetic pathways of H2S and their regulation by miRNAs and lncRNAs in various oncological and non-oncological disorders.
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Affiliation(s)
- Rana A. Youness
- Biochemistry Department, Faculty of Pharmacy and Biotechnology, German University in Cairo (GUC), Cairo 11835, Egypt
- Biology and Biochemistry Department, Faculty of Biotechnology, German International University (GIU), New Administrative Capital, Cairo 11835, Egypt
| | - Danira Ashraf Habashy
- Pharmacology and Toxicology Department, Faculty of Pharmacy and Biotechnology, German University in Cairo (GUC), Cairo 11835, Egypt
- Clinical Pharmacy Department, Faculty of Pharmacy and Biotechnology, German University in Cairo (GUC), Cairo 11835, Egypt
| | - Nour Khater
- Biochemistry Department, Faculty of Pharmacy and Biotechnology, German University in Cairo (GUC), Cairo 11835, Egypt
| | - Kareem Elsayed
- Biochemistry Department, Faculty of Pharmacy and Biotechnology, German University in Cairo (GUC), Cairo 11835, Egypt
| | - Alyaa Dawoud
- Biochemistry Department, Faculty of Pharmacy and Biotechnology, German University in Cairo (GUC), Cairo 11835, Egypt
| | - Sousanna Hakim
- Pharmacology and Toxicology Department, Faculty of Pharmacy and Biotechnology, German University in Cairo (GUC), Cairo 11835, Egypt
| | - Heba Nafea
- Biochemistry Department, Faculty of Pharmacy and Biotechnology, German University in Cairo (GUC), Cairo 11835, Egypt
| | - Carole Bourquin
- School of Pharmaceutical Sciences, Institute of Pharmaceutical Sciences of Western Switzerland, Department of Anaesthesiology, Pharmacology, Intensive Care and Emergency Medicine, University of Geneva, 1211 Geneva, Switzerland;
| | - Reham M. Abdel-Kader
- Pharmacology and Toxicology Department, Faculty of Pharmacy and Biotechnology, German University in Cairo (GUC), Cairo 11835, Egypt
| | - Mohamed Z. Gad
- Biochemistry Department, Faculty of Pharmacy and Biotechnology, German University in Cairo (GUC), Cairo 11835, Egypt
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9
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Quaglia A, Roberts EA, Torbenson M. Developmental and Inherited Liver Disease. MACSWEEN'S PATHOLOGY OF THE LIVER 2024:122-294. [DOI: 10.1016/b978-0-7020-8228-3.00003-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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10
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Gernez E, Lee GR, Niguet JP, Zerimech F, Bennis A, Grzych G. Nitrous Oxide Abuse: Clinical Outcomes, Pharmacology, Pharmacokinetics, Toxicity and Impact on Metabolism. TOXICS 2023; 11:962. [PMID: 38133363 PMCID: PMC10747624 DOI: 10.3390/toxics11120962] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Revised: 11/22/2023] [Accepted: 11/26/2023] [Indexed: 12/23/2023]
Abstract
The recreational use of nitrous oxide (N2O), also called laughing gas, has increased significantly in recent years. In 2022, the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) recognized it as one of the most prevalent psychoactive substances used in Europe. Chronic nitrous oxide (N2O) exposure can lead to various clinical manifestations. The most frequent symptoms are neurological (sensitive or motor disorders), but there are also other manifestations like psychiatric manifestations or cardiovascular disorders (thrombosis events). N2O also affects various neurotransmitter systems, leading to its anesthetic, analgesic, anxiolytic and antidepressant properties. N2O is very challenging to measure in biological matrices. Thus, in cases of N2O intoxication, indirect biomarkers such as vitamin B12, plasma homocysteine and plasma MMA should be explored for diagnosis and assessment. Others markers, like oxidative stress markers, could be promising but need to be further investigated.
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Affiliation(s)
- Emeline Gernez
- CHU de Lille, Centre de Biologie Pathologie Génétique, 59000 Lille, France; (E.G.); (F.Z.)
| | | | - Jean-Paul Niguet
- Service de Neurologie, Hôpital Saint Vincent de Paul–GHICL, 59000 Lille, France;
| | - Farid Zerimech
- CHU de Lille, Centre de Biologie Pathologie Génétique, 59000 Lille, France; (E.G.); (F.Z.)
| | - Anas Bennis
- Assistance Publique—Hôpitaux de Paris, Service de Neurologie, Groupe Hospitalier Universitaire Paris Sud, Hôpital Bicêtre, 94270 Le Kremlin-Bicêtre, France;
| | - Guillaume Grzych
- CHU de Lille, Centre de Biologie Pathologie Génétique, 59000 Lille, France; (E.G.); (F.Z.)
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11
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Dong B, Sun Y, Cheng B, Xue Y, Li W, Sun X. Activating transcription factor (ATF) 6 upregulates cystathionine β synthetase (CBS) expression and hydrogen sulfide (H 2S) synthesis to ameliorate liver metabolic damage. Eur J Med Res 2023; 28:540. [PMID: 38007457 PMCID: PMC10676581 DOI: 10.1186/s40001-023-01520-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2023] [Accepted: 11/09/2023] [Indexed: 11/27/2023] Open
Abstract
Activating transcription factor 6 (ATF6) is an endoplasmic reticulum stress responsive gene. We previously reported that conditional knockout of hepatic ATF6 exacerbated liver metabolic damage by repressing autophagy through mTOR pathway. However, the mechanism by which ATF6 influence liver metabolism has not been well established. Hydrogen sulfide (H2S) is a gaseous signaling molecule that plays an important role in regulating inflammation, and suppress nonalcoholic fatty liver in mice. Based on the previous study, we assumed that ATF6 may regulate H2S production to participate in liver metabolism. In order to clarify the mechanism by which ATF6 regulates H2S synthesis to ameliorate liver steatosis and inflammatory environment, we conducted the present study. We used the liver specific ATF6 knockout mice and fed on high-fat-diet, and found that H2S level was significantly downregulated in hepatic ATF6 knockout mice. Restoring H2S by the administration of slow H2S releasing agent GYY4137 ameliorated the hepatic steatosis and glucose tolerance. ATF6 directly binds to the promoter of cystathionine β synthetase (CBS), an important enzyme in H2S synthesis. Thus, ATF6 could upregulate H2S production through CBS. Sulfhydrated Sirtuin-1 (SIRT1) was downregulated in ATF6 knockout mice. The expression of pro-inflammatory factor IL-17A was upregulated and anti-inflammatory factor IL-10 was downregulated in ATF6 knockout mice. Our results suggest that ATF6 can transcriptionally enhance CBS expression as well as H2S synthesis. ATF6 increases SIRT1 sulfhydration and ameliorates lipogenesis and inflammation in the fatty liver. Therefore, ATF6 could be a novel therapeutic strategy for high-fat diet induced fatty liver metabolic abnormalities.
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Affiliation(s)
- Bingzi Dong
- Department of Endocrinology and Metabolic Diseases, The Affiliated Hospital of Qingdao University, Qingdao, 266003, China
| | - Ying Sun
- Health Management Center, The Affiliated Hospital of Qingdao University, Qingdao, 266003, China
| | - Bingfei Cheng
- Department of Endocrinology and Metabolic Diseases, The Affiliated Hospital of Qingdao University, Qingdao, 266003, China
| | - Yu Xue
- Department of Endocrinology and Metabolic Diseases, The Affiliated Hospital of Qingdao University, Qingdao, 266003, China
| | - Wei Li
- Interventional Medical Center, The Affiliated Hospital of Qingdao University, Qingdao, 266003, China
| | - Xiaofang Sun
- Department of Endocrinology and Metabolic Diseases, The Affiliated Hospital of Qingdao University, Qingdao, 266003, China.
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12
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Pesti-Asbóth G, Szilágyi E, Bíróné Molnár P, Oláh J, Babinszky L, Czeglédi L, Cziáky Z, Paholcsek M, Stündl L, Remenyik J. Monitoring physiological processes of fast-growing broilers during the whole life cycle: Changes of redox-homeostasis effected to trassulfuration pathway predicting the development of non-alcoholic fatty liver disease. PLoS One 2023; 18:e0290310. [PMID: 37590293 PMCID: PMC10434899 DOI: 10.1371/journal.pone.0290310] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Accepted: 08/06/2023] [Indexed: 08/19/2023] Open
Abstract
In the broiler industry, the average daily gain and feed conversion ratio are extremely favorable, but the birds are beginning to approach the maximum of their genetic capacity. However, as a consequence of strong genetic selection, the occurrence of certain metabolic diseases, such as myopathies, ascites, sudden cardiac death and tibial dyschondroplasia, is increasing. These metabolic diseases can greatly affect the health status and welfare of birds, as well as the quality of meat. The main goal of this study was to investigate the changes in the main parameters of redox homeostasis during the rearing (1-42 days of age) of broilers with high genetic capacity, such as the concentrations of malondialdehyde, vitamin C, vitamin E, and reduced glutathione, the activities of glutathione peroxidase and glutathione reductase, and the inhibition rate of superoxide dismutase. Damage to the transsulfuration pathway during growth and the reason for changes in the level of homocysteine were investigated. Further, the parameters that can characterize the biochemical changes occurring in the birds were examined. Our study is the first characterize plasma albumin saturation. A method was developed to measure the levels of other small molecule thiol components of plasma. Changes in redox homeostasis induce increases in the concentrations of tumor necrosis factor alpha and inflammatory interleukins interleukin 2, interleukin 6 and interleukin 8 in broilers reared according to current large-scale husbandry technology and feeding protocols. A significant difference in all parameters tested was observed on the 21st day. The concentrations of cytokines and homocysteine increased, while the concentrations of glutathione and cysteine in the plasma decreased. Our findings suggest that observed changes in the abovementioned biochemical indices have a negative effect on poultry health.
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Affiliation(s)
- Georgina Pesti-Asbóth
- Faculty of Agricultural and Food Sciences and Environmental Management, Institute of Food Technology, University of Debrecen, Debrecen, Hungary
| | - Endre Szilágyi
- Faculty of Agricultural and Food Sciences and Environmental Management, Institute of Food Technology, University of Debrecen, Debrecen, Hungary
| | - Piroska Bíróné Molnár
- Faculty of Agricultural and Food Sciences and Environmental Management, Institute of Food Technology, University of Debrecen, Debrecen, Hungary
| | - János Oláh
- Farm and Regional Research Institute of Debrecen, University of Debrecen, Debrecen, Hungary
| | - László Babinszky
- Faculty of Agricultural and Food Sciences and Environmental Management, Department of Animal Nutrition Physiology, Institute of Animal Science, Biotechnology and Nature Conservation, University of Debrecen, Debrecen, Hungary
| | - Levente Czeglédi
- Faculty of Agricultural and Food Sciences and Environmental Management, Department of Animal Science, Institute of Animal Science, Biotechnology and Nature Conservation, University of Debrecen, Debrecen, Hungary
| | - Zoltán Cziáky
- Agricultural and Molecular Research and Service Group, University of Nyíregyháza; Nyíregyháza, Hungary
| | - Melinda Paholcsek
- Faculty of Agricultural and Food Sciences and Environmental Management, Institute of Food Technology, University of Debrecen, Debrecen, Hungary
| | - László Stündl
- Faculty of Agricultural and Food Sciences and Environmental Management, Institute of Food Technology, University of Debrecen, Debrecen, Hungary
| | - Judit Remenyik
- Faculty of Agricultural and Food Sciences and Environmental Management, Institute of Food Technology, University of Debrecen, Debrecen, Hungary
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13
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Peng H, Zhu M, Kong W, Tang C, Du J, Huang Y, Jin H. L-cystathionine protects against oxidative stress and DNA damage induced by oxidized low-density lipoprotein in THP-1-derived macrophages. Front Pharmacol 2023; 14:1161542. [PMID: 37560474 PMCID: PMC10408194 DOI: 10.3389/fphar.2023.1161542] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Accepted: 07/13/2023] [Indexed: 08/11/2023] Open
Abstract
Introduction: Oxidative stress in monocyte-derived macrophages is a significant pathophysiological process in atherosclerosis. L-cystathionine (L-Cth) acts as a scavenger for oxygen free radicals. However, the impact of L-Cth on macrophage oxidative stress during atherogenesis has remained unclear. This study aimed to investigate whether L-Cth affects oxidative stress in THP-1-derived macrophages and its subsequent effects on DNA damage and cell apoptosis. Methods: We established a cellular model of oxLDL-stimulated macrophages. The content of superoxide anion, H2O2, NO, and H2S in the macrophage were in situ detected by the specific fluorescence probe, respectively. The activities of SOD, GSH-Px, and CAT were measured by colorimetrical assay. The protein expressions of SOD1, SOD2, and iNOS were detected using western blotting. The DNA damage and apoptosis in the macrophage was evaluated using an fluorescence kit. Results: The results demonstrated that oxLDL significantly increased the content of superoxide anion and H2O2, the expression of iNOS protein, and NO production in macrophages. Conversely, oxLDL decreased the activity of antioxidants GSH-Px, SOD, and CAT, and downregulated the protein expressions of SOD1 and SOD2 in macrophages. However, treatment with L-Cth reduced the levels of superoxide anion, H2O2, and NO, as well as the protein expression of iNOS induced by oxLDL. Moreover, L-Cth treatment significantly enhanced GSH-Px, SOD, and CAT activity, and upregulated the expressions of SOD1 and SOD2 proteins in macrophages treated with oxLDL. Furthermore, both L-Cth supplementation and activation of endogenous L-Cth production suppressed DNA damage and cell apoptosis in oxLDL-injured macrophages, whereas inhibition of endogenous L-Cth exacerbated the deleterious effects of oxLDL. Conclusion: These findings suggest that L-Cth exerts a pronounced inhibitory effect on the oxidative stress, subsequent DNA damage and cell apoptosis in oxLDL-stimulated THP-1 monocytes. This study deepens our understanding of the pathogenesis of macrophage-related cardiovascular pathology.
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Affiliation(s)
- Hanlin Peng
- Department of Pediatrics, Peking University First Hospital, Beijing, China
| | - Mingzhu Zhu
- Department of Pediatrics, Peking University First Hospital, Beijing, China
| | - Wei Kong
- Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing, China
| | - Chaoshu Tang
- Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing, China
- State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China
| | - Junbao Du
- Department of Pediatrics, Peking University First Hospital, Beijing, China
- State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China
| | - Yaqian Huang
- Department of Pediatrics, Peking University First Hospital, Beijing, China
| | - Hongfang Jin
- Department of Pediatrics, Peking University First Hospital, Beijing, China
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14
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Elkhateeb N, Hyde S, Hogg SL, Allsop D, Shankar A, Deegan P, Tan CY. Paracetamol toxicity in classic homocystinuria: Effect of N-acetylcysteine on total homocysteine. JIMD Rep 2023; 64:238-245. [PMID: 37151359 PMCID: PMC10159864 DOI: 10.1002/jmd2.12363] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2022] [Revised: 02/18/2023] [Accepted: 02/22/2023] [Indexed: 03/06/2023] Open
Abstract
Classical homocystinuria (HCU) is caused by cystathionine β-synthase deficiency leading to impaired homocysteine transsulfuration and accumulation of homocysteine and methionine. Patients present with a wide spectrum of manifestations including ocular, skeletal, neuropsychiatric, and vascular manifestations. We report a 48-year-old female with pyridoxine-unresponsive HCU treated with betaine, cyanocobalamin, and folate. Her diet was non-restricted due to intolerance of low-methionine diet. She was admitted to hospital following a fall, with multiple fractures and subsequently developed acute liver failure with encephalopathy. Shock, sepsis, and liver ischaemia/thrombosis were excluded. In the context of glutathione depletion expected in HCU, hepatic dysfunction was presumed to be due to iatrogenic paracetamol toxicity, despite paracetamol intake at conventional therapeutic dose, with role of hypermethioninemia as a contributing factor being uncertain. Betaine was discontinued on hospital admission. N-Acetylcysteine (NAC) infusion was initiated. Plasma total homocysteine (tHcy) was 3.4 μmol/L 9 days following initiation of NAC treatment with a markedly elevated plasma methionine of 1278 μmol/L. tHcy concentration returned to pre-admission baseline after NAC was discontinued. Recovery following this episode was slow with a prolonged cholestatic phase and gradual improvement in jaundice and coagulopathy. We recommend that paracetamol should be administered cautiously in HCU patients due to underlying glutathione depletion and risk of toxicity even at therapeutic doses. NAC is clearly effective in lowering tHcy in classical HCU in the short-term however further research is required to assess clinical efficacy and use as a potential therapy in classical HCU.
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Affiliation(s)
- Nour Elkhateeb
- Department of Metabolic MedicineCambridge University hospitals NHS Foundation TrustCambridgeUK
- Department of Clinical GeneticsCambridge University hospitals NHS Foundation TrustCambridgeUK
| | - Sarah Hyde
- Department of GastroenterologyNorfolk and Norwich University Hospital NHS TrustNorwichUK
| | - Sarah L. Hogg
- Biochemical Genetics UnitCambridge University Hospitals NHS Foundation TrustCambridgeUK
| | - Daniel Allsop
- Department of HistopathologyNorfolk and Norwich University Hospitals NHS TrustNorwichUK
| | - Arun Shankar
- Department of GastroenterologyNorfolk and Norwich University Hospital NHS TrustNorwichUK
| | - Patrick Deegan
- Department of Metabolic MedicineCambridge University hospitals NHS Foundation TrustCambridgeUK
| | - Chong Y. Tan
- Department of Metabolic MedicineCambridge University hospitals NHS Foundation TrustCambridgeUK
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15
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Lambooy S, Heida A, Joschko C, Nakladal D, van Buiten A, Kloosterhuis N, Huijkman N, Gerding A, van de Sluis B, Henning R, Deelman L. Selective Hepatic Cbs Knockout Aggravates Liver Damage, Endothelial Dysfunction and ROS Stress in Mice Fed a Western Diet. Int J Mol Sci 2023; 24:ijms24087019. [PMID: 37108182 PMCID: PMC10138434 DOI: 10.3390/ijms24087019] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Revised: 04/07/2023] [Accepted: 04/08/2023] [Indexed: 04/29/2023] Open
Abstract
Cystathionine-β-synthase (CBS) is highly expressed in the liver, and deficiencies in Cbs lead to hyperhomocysteinemia (HHCy) and disturbed production of antioxidants such as hydrogen sulfide. We therefore hypothesized that liver-specific Cbs deficient (LiCKO) mice would be particularly susceptible to the development of non-alcoholic fatty liver disease (NAFLD). NAFLD was induced by a high-fat high-cholesterol (HFC) diet; LiCKO and controls were split into eight groups based on genotype (con, LiCKO), diet (normal diet, HFC), and diet duration (12 weeks, 20 weeks). LiCKO mice displayed intermediate to severe HHCy. Plasma H2O2 was increased by HFC, and further aggravated in LiCKO. LiCKO mice fed an HFC diet had heavier livers, increased lipid peroxidation, elevated ALAT, aggravated hepatic steatosis, and inflammation. LiCKO mice showed decreased L-carnitine in the liver, but this did not result in impaired fatty acid oxidation. Moreover, HFC-fed LiCKO mice demonstrated vascular and renal endothelial dysfunction. Liver and endothelial damage correlated significantly with systemic ROS status. In conclusion, this study demonstrates an important role for CBS in the liver in the development of NAFLD, which is most probably mediated through impaired defense against oxidative stress.
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Affiliation(s)
- Sebastiaan Lambooy
- Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, 9713GZ Groningen, The Netherlands
| | - Andries Heida
- Department of Pediatrics, University Medical Center Groningen, University of Groningen, 9713GZ Groningen, The Netherlands
| | - Christian Joschko
- Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, 9713GZ Groningen, The Netherlands
| | - Dalibor Nakladal
- Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, 9713GZ Groningen, The Netherlands
| | - Azuwerus van Buiten
- Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, 9713GZ Groningen, The Netherlands
| | - Niels Kloosterhuis
- Department of Pediatrics, University Medical Center Groningen, University of Groningen, 9713GZ Groningen, The Netherlands
| | - Nicolette Huijkman
- Department of Pediatrics, University Medical Center Groningen, University of Groningen, 9713GZ Groningen, The Netherlands
| | - Albert Gerding
- Department of Laboratory Medicine, University Medical Center Groningen, University of Groningen, 9713GZ Groningen, The Netherlands
| | - Bart van de Sluis
- Department of Pediatrics, University Medical Center Groningen, University of Groningen, 9713GZ Groningen, The Netherlands
| | - Robert Henning
- Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, 9713GZ Groningen, The Netherlands
| | - Leo Deelman
- Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, 9713GZ Groningen, The Netherlands
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16
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Xu W, Cui C, Cui C, Chen Z, Zhang H, Cui Q, Xu G, Fan J, Han Y, Tang L, Targher G, Byrne CD, Zheng M, Yang L, Cai J, Geng B. Hepatocellular cystathionine γ lyase/hydrogen sulfide attenuates nonalcoholic fatty liver disease by activating farnesoid X receptor. Hepatology 2022; 76:1794-1810. [PMID: 35586979 PMCID: PMC9795901 DOI: 10.1002/hep.32577] [Citation(s) in RCA: 46] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Revised: 05/12/2022] [Accepted: 05/15/2022] [Indexed: 12/30/2022]
Abstract
BACKGROUND AND AIMS Hydrogen sulfide (H2 S) plays a protective role in NAFLD. However, whether cystathionine γ lyase (CSE), a dominant H2 S generating enzyme in hepatocytes, has a role in the pathogenesis of NAFLD is currently unclear. APPROACH AND RESULTS We showed that CSE protein expression is dramatically downregulated, especially in fibrotic areas, in livers from patients with NAFLD. In high-fat diet (HFD)-induced NAFLD mice or an oleic acid-induced hepatocyte model, the CSE/H2 S pathway is also downregulated. To illustrate a regulatory role for CSE in NAFLD, we generated a hepatocyte-specific CSE knockout mouse (CSELKO ). Feeding an HFD to CSELKO mice, they showed more hepatic lipid deposition with increased activity of the fatty acid de novo synthesis pathway, increased hepatic insulin resistance, and higher hepatic gluconeogenic ability compared to CSELoxp control mice. By contrast, H2 S donor treatment attenuated these phenotypes. Furthermore, the protection conferred by H2 S was blocked by farnesoid X receptor (FXR) knockdown. Consistently, serum deoxycholic acid and lithocholic acid (FXR antagonists) were increased, and tauro-β-muricholic acid (FXR activation elevated) was reduced in CSELKO . CSE/H2 S promoted a post-translation modification (sulfhydration) of FXR at Cys138/141 sites, thereby enhancing its activity to modulate expression of target genes related to lipid and glucose metabolism, inflammation, and fibrosis. Sulfhydration proteomics in patients' livers supported the CSE/H2 S modulation noted in the CSELKO mice. CONCLUSIONS FXR sulfhydration is a post-translational modification affected by hepatic endogenous CSE/H2 S that may promote FXR activity and attenuate NAFLD. Hepatic CSE deficiency promotes development of nonalcoholic steatohepatitis. The interaction between H2 S and FXR may be amenable to therapeutic drug treatment in NAFLD.
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Affiliation(s)
- Wenjing Xu
- Department of Pathology, School of Basic Medical ScienceXi'an Medical UniversityShanxiChina
| | - Changting Cui
- Hypertension Center, State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular DiseasesFuwai Hospital of Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Chunmei Cui
- Department of Bioinformatics, Physiology and Pathophysiology, School of Basic Medical SciencesPeking UniversityBeijingChina
| | - Zhenzhen Chen
- Hypertension Center, State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular DiseasesFuwai Hospital of Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Haizeng Zhang
- Hypertension Center, State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular DiseasesFuwai Hospital of Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Qinghua Cui
- Department of Bioinformatics, Physiology and Pathophysiology, School of Basic Medical SciencesPeking UniversityBeijingChina
| | - Guoheng Xu
- Department of Bioinformatics, Physiology and Pathophysiology, School of Basic Medical SciencesPeking UniversityBeijingChina
| | - Jianglin Fan
- Department of Pathology, School of Basic Medical ScienceXi'an Medical UniversityShanxiChina
| | - Yu Han
- Department of Gastrointestinal Surgerythe First Affiliated Hospital of Wenzhou Medical UniversityWenzhouChina
| | - Liangjie Tang
- NAFLD Research Center, Department of Hepatologythe First Affiliated Hospital of Wenzhou Medical University; the Key Laboratory of Diagnosis and Treatment for the Development of Chronic Liver Disease in Zhejiang ProvinceWenzhouChina
| | - Giovanni Targher
- Section of Endocrinology, Diabetes and Metabolism, Department of MedicineUniversity and Azienda Ospedaliera Universitaria Integrata of VeronaVeronaItaly
| | - Christopher D. Byrne
- Southampton National Institute for Health and Care Research Biomedical Research CentreUniversity Hospital Southampton, Southampton General HospitalSouthamptonUK
| | - Ming‐Hua Zheng
- NAFLD Research Center, Department of Hepatologythe First Affiliated Hospital of Wenzhou Medical University; the Key Laboratory of Diagnosis and Treatment for the Development of Chronic Liver Disease in Zhejiang ProvinceWenzhouChina
| | - Liming Yang
- Department of PathophysiologyHarbin Medical University‐DaqingDaqingChina
| | - Jun Cai
- Hypertension Center, State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular DiseasesFuwai Hospital of Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Bin Geng
- Hypertension Center, State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular DiseasesFuwai Hospital of Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
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17
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Skeletal Muscle CSE Deficiency Leads to Insulin Resistance in Mice. Antioxidants (Basel) 2022; 11:antiox11112216. [PMID: 36358588 PMCID: PMC9687043 DOI: 10.3390/antiox11112216] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Revised: 10/28/2022] [Accepted: 11/07/2022] [Indexed: 11/11/2022] Open
Abstract
Cystathionine-γ-lyase (CSE) is expressed in various tissues and generates H2S via an alternative desulfuration reaction. We sought to explore the functions of skeletal muscle CSE using skeletal muscle conditional knockout CSE (MCSEKO) mice. It was found that body weight, muscle morphology, and exercise capacity were not altered in MCSEKO mice compared with littermate wild-type mice. RNA-seq-based transcriptome analysis showed that 275 genes were differentially regulated in skeletal muscle and multiple signaling pathways including insulin signaling and mTOR, PI3K-AKT, and cGMP-PKG signaling pathways were enriched in MCSEKO mice. The intraperitoneal glucose tolerance test and insulin tolerance test showed that glucose tolerance and insulin sensitivity were reduced in MCSEKO mice. Glucose transporter 4 (GLU4) and PKG-1 expression levels and insulin receptor substrate-1(IRS1)/PI3K/Akt signaling pathway were downregulated whilst the mTOR/S6K/S6 pathway was enhanced in MCSEKO mice. These effects were reversed by the H2S supplement. Aerobic treadmill training significantly promoted glucose tolerance and insulin sensitivity and improved GLU4 and PKG-1 levels, promoted IRS1/PI3K/Akt signaling and suppressed mTOR/S6K/S6 signaling pathway in MCSEKO mice. Our data suggest that skeletal muscle CSE/H2S signaling is critical for the maintenance of insulin sensitivity, which is associated with maintaining the balance in PKG, PI3K/Akt, and mTOR/S6K/S6 signaling pathways in skeletal muscle.
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18
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Lee JH, Im SS. Function of gaseous hydrogen sulfide in liver fibrosis. BMB Rep 2022; 55:481-487. [PMID: 36195563 PMCID: PMC9623240 DOI: 10.5483/bmbrep.2022.55.10.124] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 09/07/2022] [Accepted: 09/21/2022] [Indexed: 11/06/2022] Open
Abstract
Over the past few years, hydrogen sulfide (H2S) has been shown to exert several biological functions in mammalian. The endogenous production of H2S is mainly mediated by cystathione β-synthase, cystathione γ-lyase and 3-mercaptopyruvate sulfur transferase. These enzymes are broadly expressed in liver tissue and regulates liver function by working on a variety of molecular targets. As an important regulator of liver function, H2S is critically involved in the pathogenesis of various liver diseases, such as non-alcoholic steatohepatitis and liver cancer. Targeting H2S-generating enzymes may be a therapeutic strategy for controlling liver diseases. This review described the function of H2S in liver disease and summarized recent characterized role of H2S in several cellular process of the liver. [BMB Reports 2022; 55(10): 481-487].
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Affiliation(s)
- Jae-Ho Lee
- Department of Physiology, Keimyung University School of Medicine, Daegu 42601, Korea
| | - Seung-Soon Im
- Department of Physiology, Keimyung University School of Medicine, Daegu 42601, Korea
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19
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Abdel-Latif R, Heeba GH, Hassanin SO, Waz S, Amin A. TLRs-JNK/ NF-κB Pathway Underlies the Protective Effect of the Sulfide Salt Against Liver Toxicity. Front Pharmacol 2022; 13:850066. [PMID: 35517830 PMCID: PMC9065287 DOI: 10.3389/fphar.2022.850066] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Accepted: 03/11/2022] [Indexed: 12/11/2022] Open
Abstract
Hydrogen sulfide (H2S) is an endogenously gas transmitter signaling molecule with known antioxidant, anti-inflammatory, and cytoprotective properties. Although accumulating evidence shows the therapeutic potential of H2S in various hepatic diseases, its role in cyclophosphamide (CP)-induced hepatotoxicity remains elusive. The present study was undertaken to investigate the impact of endogenous and exogenous H2S on toll-like receptors (TLRs)-mediated inflammatory response and apoptosis in CP-induced hepatotoxicity. Either an H2S donor (NaHS (100 μM/kg) or an H2S blocker [dl-propargylglycine (PAG) (30 mg/kg, i. p.)], was administered for 10 days before a single ip injection of CP (200 mg/kg). NaHS attenuated conferred hepatoprotection against CP-induced toxicity, significantly decreasing serum hepatic function tests and improving hepatic histopathology. Additionally, NaHS-treated rats exhibited antioxidant activity in liver tissues compared with the CP group. The upregulated hepatic levels of TLR2/4 and their downstream signaling molecules including c-Jun N-terminal kinase (JNK) and nuclear factor-kappa B (NF-κB) were also suppressed by NaHS protective treatment. NaHS showed anti-inflammatory and antiapoptotic effects; reducing hepatic level tumor necrosis factor-alpha (TNF-α) and caspase-3 expression. Interestingly, the cytotoxic events induced in CP-treated rats were not significantly altered upon the blocking of endogenous H2S. Taken together, the present study suggested that exogenously applied H2S rather than the endogenously generated H2S, displayed a hepatoprotective effect against CP-induced hepatotoxicity that might be mediated by TLRs-JNK/NF-κB pathways.
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Affiliation(s)
- Rania Abdel-Latif
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, El-Minia, Egypt
| | - Gehan Hussein Heeba
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, El-Minia, Egypt
| | - Soha Osama Hassanin
- Department of Biochemistry, Faculty of Pharmacy, MTI University, Cairo, Egypt
| | - Shaimaa Waz
- Department of Biochemistry, Faculty of Pharmacy, Minia University, El-Minia, Egypt
| | - Amr Amin
- The College, The University of Chicago, Chicago, IL, United States.,Department of Biology, UAE University, Al Ain, United Arab Emirates
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20
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Wang H, Wu Y, Tang W. Methionine cycle in nonalcoholic fatty liver disease and its potential applications. Biochem Pharmacol 2022; 200:115033. [PMID: 35395242 DOI: 10.1016/j.bcp.2022.115033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Revised: 03/31/2022] [Accepted: 03/31/2022] [Indexed: 11/25/2022]
Abstract
As a chronic metabolic disease affecting epidemic proportions worldwide, the pathogenesis of Nonalcoholic Fatty Liver Disease (NAFLD) is not clear yet. There is also a lack of precise biomarkers and specific medicine for the diagnosis and treatment of NAFLD. Methionine metabolic cycle, which is critical for the maintaining of cellular methylation and redox state, is involved in the pathophysiology of NAFLD. However, the molecular basis and mechanism of methionine metabolism in NAFLD are not completely understood. Here, we mainly focus on specific enzymes that participates in methionine cycle, to reveal their interconnections with NAFLD, in order to recognize the pathogenesis of NAFLD from a new angle and at the same time, explore the clinical characteristics and therapeutic strategies.
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Affiliation(s)
- Haoyu Wang
- University of Chinese Academy of Sciences, Beijing, 100049, PR China; Laboratory of Anti-inflammation, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China
| | - Yanwei Wu
- Laboratory of Anti-inflammation, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China
| | - Wei Tang
- University of Chinese Academy of Sciences, Beijing, 100049, PR China; Laboratory of Anti-inflammation, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China.
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21
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Nakladal D, Lambooy SPH, Mišúth S, Čepcová D, Joschko CP, Buiten A, Goris M, Hoogstra‐Berends F, Kloosterhuis NJ, Huijkman N, Sluis B, Diercks GF, Buikema JH, Henning RH, Deelman LE. Homozygous whole body
Cbs
knockout in adult mice features minimal pathology during ageing despite severe homocysteinemia. FASEB J 2022; 36:e22260. [DOI: 10.1096/fj.202101550r] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 02/17/2022] [Accepted: 03/07/2022] [Indexed: 11/11/2022]
Affiliation(s)
- D. Nakladal
- Department of Clinical Pharmacy and Pharmacology University of Groningen University Medical Center Groningen Groningen The Netherlands
| | - S. P. H. Lambooy
- Department of Clinical Pharmacy and Pharmacology University of Groningen University Medical Center Groningen Groningen The Netherlands
| | - S. Mišúth
- Department of Clinical Pharmacy and Pharmacology University of Groningen University Medical Center Groningen Groningen The Netherlands
- Department of Pharmacology & Toxicology Faculty of Pharmacy Comenius University in Bratislava Bratislava Slovakia
| | - D. Čepcová
- Department of Clinical Pharmacy and Pharmacology University of Groningen University Medical Center Groningen Groningen The Netherlands
- Department of Pharmacology & Toxicology Faculty of Pharmacy Comenius University in Bratislava Bratislava Slovakia
| | - C. P. Joschko
- Department of Clinical Pharmacy and Pharmacology University of Groningen University Medical Center Groningen Groningen The Netherlands
| | - A. Buiten
- Department of Clinical Pharmacy and Pharmacology University of Groningen University Medical Center Groningen Groningen The Netherlands
| | - M. Goris
- Department of Clinical Pharmacy and Pharmacology University of Groningen University Medical Center Groningen Groningen The Netherlands
| | - F. Hoogstra‐Berends
- Department of Clinical Pharmacy and Pharmacology University of Groningen University Medical Center Groningen Groningen The Netherlands
| | - N. J. Kloosterhuis
- Department of Pediatrics University of Groningen University Medical Center Groningen Groningen The Netherlands
| | - N. Huijkman
- iPSC/CRISPR Center Groningen University of Groningen University Medical Center Groningen Groningen The Netherlands
| | - B. Sluis
- Department of Pediatrics University of Groningen University Medical Center Groningen Groningen The Netherlands
- iPSC/CRISPR Center Groningen University of Groningen University Medical Center Groningen Groningen The Netherlands
| | - G. F. Diercks
- Department of Dermatology Center for Blistering Diseases University of Groningen University Medical Center Groningen Groningen The Netherlands
| | - J. H. Buikema
- Department of Clinical Pharmacy and Pharmacology University of Groningen University Medical Center Groningen Groningen The Netherlands
| | - R. H. Henning
- Department of Clinical Pharmacy and Pharmacology University of Groningen University Medical Center Groningen Groningen The Netherlands
| | - L. E. Deelman
- Department of Clinical Pharmacy and Pharmacology University of Groningen University Medical Center Groningen Groningen The Netherlands
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22
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Mateus I, Prip-Buus C. Hydrogen sulphide in liver glucose/lipid metabolism and non-alcoholic fatty liver disease. Eur J Clin Invest 2022; 52:e13680. [PMID: 34519030 PMCID: PMC9285505 DOI: 10.1111/eci.13680] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 08/24/2021] [Accepted: 09/10/2021] [Indexed: 12/13/2022]
Abstract
BACKGROUND For a long time, hydrogen sulphide (H2 S) was considered only as a toxic gas, inhibiting mitochondrial respiration at the level of cytochrome c oxidase, and an environmental pollutant. Nowadays, H2 S is recognized as the third mammalian gasotransmitter, playing an important role in inflammation, septic shock, ischaemia reperfusion events, cardiovascular disease and more recently in liver physiology and chronic liver diseases such as non-alcoholic fatty liver disease (NAFLD). METHODS This narrative review is based on literature search using PubMed. RESULTS From a bioenergetic perspective, H2 S is a very unique molecule, serving as a mitochondrial poison at high concentrations or as an inorganic mitochondrial substrate at low concentrations. By using transgenic animal models to specifically modulate liver H2 S biosynthesis or exogenous compounds that release H2 S, several studies demonstrated that H2 S is a key player in liver glucose and lipid metabolism. Liver H2 S content and biosynthesis were also altered in NAFLD animal models with the in vivo administration of H2 S-releasing molecules preventing the further escalation into non-alcoholic-steatohepatitis. Liver steady-state levels of H2 S, and hence its cell signalling properties, are controlled by a tight balance between its biosynthesis, mainly through the transsulphuration pathway, and its mitochondrial oxidation via the sulphide oxidizing unit. However, studies investigating mitochondrial H2 S oxidation in liver dysfunction still remain scarce. CONCLUSIONS Since H2 S emerges as a key regulator of liver metabolism and metabolic flexibility, further understanding the physiological relevance of mitochondrial H2 S oxidation in liver energy homeostasis and its potential implication in chronic liver diseases are of great interest.
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Affiliation(s)
- Inês Mateus
- Institut Cochin, INSERM, CNRS, Université de Paris, Paris, France
| | - Carina Prip-Buus
- Institut Cochin, INSERM, CNRS, Université de Paris, Paris, France
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23
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Arif HM, Qian Z, Wang R. Signaling Integration of Hydrogen Sulfide and Iron on Cellular Functions. Antioxid Redox Signal 2022; 36:275-293. [PMID: 34498949 DOI: 10.1089/ars.2021.0203] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Significance: Hydrogen sulfide (H2S) is an endogenous signaling molecule, regulating numerous physiological functions from vasorelaxation to neuromodulation. Iron is a well-known bioactive metal ion, being the central component of hemoglobin for oxygen transportation and participating in biomolecule degradation, redox balance, and enzymatic actions. The interplay between H2S and iron metabolisms and functions impacts significantly on the fate and wellness of different types of cells. Recent Advances: Iron level in vivo affects the production of H2S via nonenzymatic reactions. On the contrary, H2S quenches excessive iron inside the cells and regulates the redox status of iron. Critical Issues: Abnormal metabolisms of both iron and H2S are associated with various conditions and diseases such as iron overload, anemia, oxidative stress, and cardiovascular and neurodegenerative diseases. The molecular mechanisms for the interactions between H2S and iron are unsettled yet. Here we review signaling links of the production, metabolism, and their respective and integrative functions of H2S and iron in normalcy and diseases. Future Directions: Physiological and pathophysiological importance of H2S and iron as well as their therapeutic applications should be evaluated jointly, not separately. Future investigation should expand from iron-rich cells and tissues to the others, in which H2S and iron interaction has not received due attention. Antioxid. Redox Signal. 36, 275-293.
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Affiliation(s)
| | - Zhongming Qian
- Institute of Translational & Precision Medicine, Nantong University, Nantong, China
| | - Rui Wang
- Department of Biology, York University, Toronto, Canada
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24
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Li W, Shen Y, Gong X, Zhang XB, Yuan L. Highly Selective Fluorescent Probe Design for Visualizing Hepatic Hydrogen Sulfide in the Pathological Progression of Nonalcoholic Fatty Liver. Anal Chem 2021; 93:16673-16682. [PMID: 34842411 DOI: 10.1021/acs.analchem.1c04246] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Hydrogen sulfide (H2S), emerging as an important gaseous signal, has attracted more and more attention for its key role in chronic fatty liver diseases. However, lacking tools for H2S-specific in situ detection, the changes of endogenous hepatic H2S levels in the pathological progression of chronic liver diseases are still unclear. To this end, we adopted a strategy of combining molecular probe design and nanofunctionalization to develop a highly selective near-infrared (NIR) fluorescent probe, which allows in vivo real-time monitoring of hepatic H2S levels in the process of nonalcoholic fatty liver disease (NAFLD). As a proof of strategy demonstration, we first designed NIR molecular probes for H2S sensing through chemical design and probe screening and then loaded molecular probes into mesoporous silicon nanomaterials (MSNs) with surface encapsulation using poly(ethylene glycol) to construct a highly selective probe MSN@CSN@PEG, with significantly improved selectivity and photostability. Moreover, MSN@CSN@PEG exhibited high selectivity and sensitivity for endogenous H2S in cells and tumors in vivo, eliminating the interference of a high concentration of biothiols and sulfhydryl proteins. Furthermore, the probe was applied to in situ intravital imaging and systematic assessment of hepatic H2S levels in different stages of NAFLD for the first time, which may offer a promising tool for the future study of fatty liver diseases and other chronic liver diseases.
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Affiliation(s)
- Wei Li
- State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, China
| | - Yang Shen
- State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, China
| | - Xiangyang Gong
- State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, China
| | - Xiao-Bing Zhang
- State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, China
| | - Lin Yuan
- State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, China
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25
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Padmanabhan N, Kyon HK, Boot A, Lim K, Srivastava S, Chen S, Wu Z, Lee HO, Mukundan VT, Chan C, Chan YK, Xuewen O, Pitt JJ, Isa ZFA, Xing M, Lee MH, Tan ALK, Ting SHW, Luftig MA, Kappei D, Kruger WD, Bian J, Ho YS, Teh M, Rozen SG, Tan P. Highly recurrent CBS epimutations in gastric cancer CpG island methylator phenotypes and inflammation. Genome Biol 2021; 22:167. [PMID: 34074348 PMCID: PMC8170989 DOI: 10.1186/s13059-021-02375-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Accepted: 05/06/2021] [Indexed: 02/06/2023] Open
Abstract
Background CIMP (CpG island methylator phenotype) is an epigenetic molecular subtype, observed in multiple malignancies and associated with the epigenetic silencing of tumor suppressors. Currently, for most cancers including gastric cancer (GC), mechanisms underlying CIMP remain poorly understood. We sought to discover molecular contributors to CIMP in GC, by performing global DNA methylation, gene expression, and proteomics profiling across 14 gastric cell lines, followed by similar integrative analysis in 50 GC cell lines and 467 primary GCs. Results We identify the cystathionine beta-synthase enzyme (CBS) as a highly recurrent target of epigenetic silencing in CIMP GC. Likewise, we show that CBS epimutations are significantly associated with CIMP in various other cancers, occurring even in premalignant gastroesophageal conditions and longitudinally linked to clinical persistence. Of note, CRISPR deletion of CBS in normal gastric epithelial cells induces widespread DNA methylation changes that overlap with primary GC CIMP patterns. Reflecting its metabolic role as a gatekeeper interlinking the methionine and homocysteine cycles, CBS loss in vitro also causes reductions in the anti-inflammatory gasotransmitter hydrogen sulfide (H2S), with concomitant increase in NF-κB activity. In a murine genetic model of CBS deficiency, preliminary data indicate upregulated immune-mediated transcriptional signatures in the stomach. Conclusions Our results implicate CBS as a bi-faceted modifier of aberrant DNA methylation and inflammation in GC and highlights H2S donors as a potential new therapy for CBS-silenced lesions. Supplementary Information The online version contains supplementary material available at 10.1186/s13059-021-02375-2.
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Affiliation(s)
- Nisha Padmanabhan
- Programme in Cancer and Stem Cell Biology, Duke-NUS Medical School, 8, College road, Singapore, 169857, Singapore
| | - Huang Kie Kyon
- Programme in Cancer and Stem Cell Biology, Duke-NUS Medical School, 8, College road, Singapore, 169857, Singapore
| | - Arnoud Boot
- Centre for Computational Biology, Duke-NUS Medical School, Singapore, 169857, Singapore
| | - Kevin Lim
- Programme in Cancer and Stem Cell Biology, Duke-NUS Medical School, 8, College road, Singapore, 169857, Singapore
| | - Supriya Srivastava
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore
| | - Shuwen Chen
- Bioprocessing Technology Institute, A*STAR, 20 Biopolis Way, #06-01 Centros, Singapore, 138668, Singapore
| | - Zhiyuan Wu
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
| | - Hyung-Ok Lee
- Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA, USA
| | - Vineeth T Mukundan
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore
| | - Charlene Chan
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore
| | - Yarn Kit Chan
- Programme in Cancer and Stem Cell Biology, Duke-NUS Medical School, 8, College road, Singapore, 169857, Singapore
| | - Ong Xuewen
- Programme in Cancer and Stem Cell Biology, Duke-NUS Medical School, 8, College road, Singapore, 169857, Singapore
| | - Jason J Pitt
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore
| | - Zul Fazreen Adam Isa
- Programme in Cancer and Stem Cell Biology, Duke-NUS Medical School, 8, College road, Singapore, 169857, Singapore
| | - Manjie Xing
- Programme in Cancer and Stem Cell Biology, Duke-NUS Medical School, 8, College road, Singapore, 169857, Singapore
| | - Ming Hui Lee
- Programme in Cancer and Stem Cell Biology, Duke-NUS Medical School, 8, College road, Singapore, 169857, Singapore
| | - Angie Lay Keng Tan
- Programme in Cancer and Stem Cell Biology, Duke-NUS Medical School, 8, College road, Singapore, 169857, Singapore
| | - Shamaine Ho Wei Ting
- Programme in Cancer and Stem Cell Biology, Duke-NUS Medical School, 8, College road, Singapore, 169857, Singapore
| | - Micah A Luftig
- Department of Molecular Genetics and Microbiology, Duke Centre for Virology, Duke University School of Medicine, Durham, NC, USA
| | - Dennis Kappei
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore.,Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117596, Singapore
| | - Warren D Kruger
- Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA, USA
| | - Jinsong Bian
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore.,National University of Singapore (Suzhou) Research Institute, Suzhou, 215123, China
| | - Ying Swan Ho
- Bioprocessing Technology Institute, A*STAR, 20 Biopolis Way, #06-01 Centros, Singapore, 138668, Singapore
| | - Ming Teh
- Department of Pathology, National University of Singapore, Singapore, 119228, Singapore
| | - Steve George Rozen
- Centre for Computational Biology, Duke-NUS Medical School, Singapore, 169857, Singapore
| | - Patrick Tan
- Programme in Cancer and Stem Cell Biology, Duke-NUS Medical School, 8, College road, Singapore, 169857, Singapore. .,Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore. .,Genome Institute of Singapore, Singapore, 138672, Singapore. .,SingHealth/Duke-NUS Institute of Precision Medicine, National Heart Centre Singapore, Singapore, 169856, Singapore. .,Singapore Gastric Cancer Consortium, Singapore, 119074, Singapore. .,Department of Physiology, National University of Singapore, Singapore, 117593, Singapore.
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26
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DiNicolantonio JJ, McCarty MF, Barroso-Aranda J, Assanga S, Lujan LML, O'Keefe JH. A nutraceutical strategy for downregulating TGFβ signalling: prospects for prevention of fibrotic disorders, including post-COVID-19 pulmonary fibrosis. Open Heart 2021; 8:openhrt-2021-001663. [PMID: 33879509 PMCID: PMC8061562 DOI: 10.1136/openhrt-2021-001663] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/30/2021] [Indexed: 12/14/2022] Open
Affiliation(s)
- James J DiNicolantonio
- Preventive Cardiology, Saint Luke's Mid America Heart Institute, Kansas City, Missouri, USA
| | | | | | - Simon Assanga
- Department of Research and Postgraduate Studies in Food, University of Sonora, Sonora, Mexico
| | | | - James H O'Keefe
- University of Missouri-Kansas City, Saint Lukes Mid America Heart Institute, Kansas City, Missouri, USA
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27
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The Role of the Transsulfuration Pathway in Non-Alcoholic Fatty Liver Disease. J Clin Med 2021; 10:jcm10051081. [PMID: 33807699 PMCID: PMC7961611 DOI: 10.3390/jcm10051081] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 02/21/2021] [Accepted: 03/01/2021] [Indexed: 02/07/2023] Open
Abstract
The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing and approximately 25% of the global population may have NAFLD. NAFLD is associated with obesity and metabolic syndrome, but its pathophysiology is complex and only partly understood. The transsulfuration pathway (TSP) is a metabolic pathway regulating homocysteine and cysteine metabolism and is vital in controlling sulfur balance in the organism. Precise control of this pathway is critical for maintenance of optimal cellular function. The TSP is closely linked to other pathways such as the folate and methionine cycles, hydrogen sulfide (H2S) and glutathione (GSH) production. Impaired activity of the TSP will cause an increase in homocysteine and a decrease in cysteine levels. Homocysteine will also be increased due to impairment of the folate and methionine cycles. The key enzymes of the TSP, cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE), are highly expressed in the liver and deficient CBS and CSE expression causes hepatic steatosis, inflammation, and fibrosis in animal models. A causative link between the TSP and NAFLD has not been established. However, dysfunctions in the TSP and related pathways, in terms of enzyme expression and the plasma levels of the metabolites (e.g., homocysteine, cystathionine, and cysteine), have been reported in NAFLD and liver cirrhosis in both animal models and humans. Further investigation of the TSP in relation to NAFLD may reveal mechanisms involved in the development and progression of NAFLD.
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28
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Sun HJ, Wu ZY, Nie XW, Bian JS. The Role of H 2S in the Metabolism of Glucose and Lipids. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1315:51-66. [PMID: 34302688 DOI: 10.1007/978-981-16-0991-6_3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Glucose and lipids are essential elements for maintaining the body's homeostasis, and their dysfunction may participate in the pathologies of various diseases, particularly diabetes, obesity, metabolic syndrome, cardiovascular ailments, and cancers. Among numerous endogenous mediators, the gasotransmitter hydrogen sulfide (H2S) plays a central role in the maintenance of glucose and lipid homeostasis. Current evidence from both pharmacological studies and transgenic animal models suggest a complex relationship between H2S and metabolic dysregulation, especially in diabetes and obesity. This notion is achieved through tissue-specific expressions and actions of H2S on target metabolic and hormone organs including the pancreas, skeletal muscle, livers, and adipose. In this chapter, we will summarize the roles and mechanisms of H2S in several metabolic organs/tissues that are necessary for glucose and lipid metabolic homeostasis. In addition, future research directions and valuable therapeutic avenues around the pharmacological regulation of H2S in glycolipid metabolism disorder will be also discussed.
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Affiliation(s)
- Hai-Jian Sun
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Zhi-Yuan Wu
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Xiao-Wei Nie
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.,Center of Clinical Research, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, China
| | - Jin-Song Bian
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. .,National University of Singapore (Suzhou) Research Institute, Suzhou, China.
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Liu Z, Liu M, Fan M, Pan S, Li S, Chen M, Wang H. Metabolomic-proteomic combination analysis reveals the targets and molecular pathways associated with hydrogen sulfide alleviating NAFLD. Life Sci 2020; 264:118629. [PMID: 33131747 DOI: 10.1016/j.lfs.2020.118629] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Revised: 10/10/2020] [Accepted: 10/17/2020] [Indexed: 01/03/2023]
Abstract
AIMS Nonalcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease worldwide. Exogenous H2S has been shown to effectively mitigate NAFLD, although little is known about the underlying targets and molecular mechanisms. METHODS C57BL/6 mice were fed with normal fat diet (NFD) or high fat diet (HFD) for a total 16 weeks, and HFD-fed mice were treated with saline or NaHS beginning in 12th week. The combination analysis of metabolomics and proteomics of liver tissues was firstly performed to discover the candidate targets and potential molecular pathways involved in H2S mitigating the NAFLD. KEY FINDINGS Compared with NaCl, H2S relieved NAFLD by reducing liver weight, body weight and lipid accumulation in liver, and improving liver pathology and serum biochemical parameters. There were 40 overlapping metabolites in the intersection analysis between comparative analysis of HFD + NaCl vs NFD and HFD + NaHS vs HFD + NaCl based on liver metabolomics. Moreover, a total of 58 proteins were obtained whose changes were reversed after treatment with H2S. A combined analysis of liver metabolomics and proteomics was then conducted, revealing 8 shared molecular pathways, as well as the enrichment of unsaturated fatty acids. In addition, Plin2 may also be a potential target of H2S via the regulation of lipid droplet degradation in alleviating NAFLD. SIGNIFICANCE We performed the first study combining metabolomics and proteomics to explore the mechanisms behind the alleviation of NAFLD by H2S. Our results not only provide evidence that H2S alleviates NAFLD but also reveals its possible molecular mechanisms and targets.
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Affiliation(s)
- Zhangnan Liu
- Joint National Laboratory for Antibody Drug Engineering, Key Laboratory of Cellular and Molecular Immunology of Henan Province, Institute of Translational Medicine, School of Basic Medicine, Henan University, Kaifeng 475004, China
| | - Meichen Liu
- Joint National Laboratory for Antibody Drug Engineering, Key Laboratory of Cellular and Molecular Immunology of Henan Province, Institute of Translational Medicine, School of Basic Medicine, Henan University, Kaifeng 475004, China
| | - Ming Fan
- Joint National Laboratory for Antibody Drug Engineering, Key Laboratory of Cellular and Molecular Immunology of Henan Province, Institute of Translational Medicine, School of Basic Medicine, Henan University, Kaifeng 475004, China
| | - Sijing Pan
- Joint National Laboratory for Antibody Drug Engineering, Key Laboratory of Cellular and Molecular Immunology of Henan Province, Institute of Translational Medicine, School of Basic Medicine, Henan University, Kaifeng 475004, China
| | - Shaowei Li
- Joint National Laboratory for Antibody Drug Engineering, Key Laboratory of Cellular and Molecular Immunology of Henan Province, Institute of Translational Medicine, School of Basic Medicine, Henan University, Kaifeng 475004, China
| | - Mingliang Chen
- School of Basic Medicine, Henan University, Kaifeng 475004, China.
| | - Huijuan Wang
- Joint National Laboratory for Antibody Drug Engineering, Key Laboratory of Cellular and Molecular Immunology of Henan Province, Institute of Translational Medicine, School of Basic Medicine, Henan University, Kaifeng 475004, China.
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Blachier F, Andriamihaja M, Blais A. Sulfur-Containing Amino Acids and Lipid Metabolism. J Nutr 2020; 150:2524S-2531S. [PMID: 33000164 DOI: 10.1093/jn/nxaa243] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Revised: 07/08/2020] [Accepted: 07/21/2020] [Indexed: 01/06/2023] Open
Abstract
The metabolism of methionine and cysteine in the body tissues determines the concentrations of several metabolites with various biologic activities, including homocysteine, hydrogen sulfide (H2S), taurine, and glutathione. Hyperhomocysteinemia, which is correlated with lower HDL cholesterol in blood in volunteers and animal models, has been associated with an increased risk for cardiovascular diseases. In humans, the relation between methionine intake and hyperhomocysteinemia is dependent on vitamin status (vitamins B-6 and B-12 and folic acid) and on the supply of other amino acids. However, lowering homocysteinemia by itself is not sufficient for decreasing the risk of cardiovascular disease progression. Other compounds related to methionine metabolism have recently been identified as being involved in the risk of atherosclerosis and steatohepatitis. Indeed, the metabolism of sulfur amino acids has an impact on phosphatidylcholine (PC) metabolism, and anomalies in PC synthesis due to global hypomethylation have been associated with disturbances of lipid metabolism. In addition, impairment of H2S synthesis from cysteine favors atherosclerosis and steatosis in animal models. The effects of taurine on lipid metabolism appear heterogeneous depending on the populations of volunteers studied. A decrease in the concentration of intracellular glutathione, a tripeptide involved in redox homeostasis, is implicated in the etiology of cardiovascular diseases and steatosis. Last, supplementation with betaine, a compound that allows remethylation of homocysteine to methionine, decreases basal and methionine-stimulated homocysteinemia; however, it adversely increases plasma total and LDL cholesterol. The study of these metabolites may help determine the range of optimal and safe intakes of methionine and cysteine in dietary proteins and supplements. The amino acid requirement for protein synthesis in different situations and for optimal production of intracellular compounds involved in the regulation of lipid metabolism also needs to be considered for dietary attenuation of atherosclerosis and steatosis risk.
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Affiliation(s)
- Francois Blachier
- Université Paris-Saclay, AgroParisTech, INRAE, UMR PNCA, 75005, Paris, France
| | | | - Anne Blais
- Université Paris-Saclay, AgroParisTech, INRAE, UMR PNCA, 75005, Paris, France
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Comas F, Latorre J, Ortega F, Oliveras-Cañellas N, Lluch A, Ricart W, Fernández-Real JM, Moreno-Navarrete JM. Permanent cystathionine-β-Synthase gene knockdown promotes inflammation and oxidative stress in immortalized human adipose-derived mesenchymal stem cells, enhancing their adipogenic capacity. Redox Biol 2020; 42:101668. [PMID: 32800520 PMCID: PMC8113015 DOI: 10.1016/j.redox.2020.101668] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Accepted: 07/29/2020] [Indexed: 12/12/2022] Open
Abstract
In the present study, we aimed to investigate the impact of permanent cystathionine-β-Synthase (CBS) gene knockdown in human telomerase reverse transcriptase (hTERT) immortalized human adipose-derived mesenchymal stem cells (ASC52telo) and in their capacity to differentiate into adipocytes. CBS gene KD in ASC52telo cells led to increased cellular inflammation (IL6, CXCL8, TNF) and oxidative stress markers (increased intracellular reactive oxygen species and decreased reduced glutathione levels) in parallel to decreased H2S production and rejuvenation (LC3 and SIRT1)-related gene expression. In addition, CBS gene KD in ASC52telo cells resulted in altered mitochondrial respiratory function, characterised by decreased basal respiration (specifically proton leak) and spare respiratory capacity, without significant effects on cell viability and proliferation. In this context, shCBS-ASC52telo cells displayed enhanced adipogenic (FABP4, ADIPOQ, SLC2A4, CEBPA, PPARG)-, lipogenic (FASN, DGAT1)- and adipocyte (LEP, LBP)-related gene expression markers, decreased expression of proinflammatory cytokines, and increased intracellular lipid accumulation during adipocyte differentiation compared to control ASC52telo cells. Otherwise, the increased adipogenic potential of shCBS-ASC52telo cells was detrimental to the ability to differentiate into osteogenic linage. In conclusion, this study demonstrated that permanent CBS gene KD in ASC52telo cells promotes a cellular senescence phenotype with a very increased adipogenic potential, promoting a non-physiological enhanced adipocyte differentiation with excessive lipid storage.
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Affiliation(s)
- Ferran Comas
- Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona (IdIBGi), CIBEROBN (CB06/03/010) and Instituto de Salud Carlos III (ISCIII), Girona, Spain
| | - Jèssica Latorre
- Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona (IdIBGi), CIBEROBN (CB06/03/010) and Instituto de Salud Carlos III (ISCIII), Girona, Spain
| | - Francisco Ortega
- Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona (IdIBGi), CIBEROBN (CB06/03/010) and Instituto de Salud Carlos III (ISCIII), Girona, Spain
| | - Núria Oliveras-Cañellas
- Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona (IdIBGi), CIBEROBN (CB06/03/010) and Instituto de Salud Carlos III (ISCIII), Girona, Spain
| | - Aina Lluch
- Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona (IdIBGi), CIBEROBN (CB06/03/010) and Instituto de Salud Carlos III (ISCIII), Girona, Spain
| | - Wifredo Ricart
- Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona (IdIBGi), CIBEROBN (CB06/03/010) and Instituto de Salud Carlos III (ISCIII), Girona, Spain
| | - José Manuel Fernández-Real
- Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona (IdIBGi), CIBEROBN (CB06/03/010) and Instituto de Salud Carlos III (ISCIII), Girona, Spain; Department of Medicine, Universitat de Girona, Girona, Spain.
| | - José María Moreno-Navarrete
- Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona (IdIBGi), CIBEROBN (CB06/03/010) and Instituto de Salud Carlos III (ISCIII), Girona, Spain; Department of Medicine, Universitat de Girona, Girona, Spain.
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Sun HJ, Wu ZY, Nie XW, Wang XY, Bian JS. Implications of hydrogen sulfide in liver pathophysiology: Mechanistic insights and therapeutic potential. J Adv Res 2020; 27:127-135. [PMID: 33318872 PMCID: PMC7728580 DOI: 10.1016/j.jare.2020.05.010] [Citation(s) in RCA: 59] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Revised: 05/06/2020] [Accepted: 05/07/2020] [Indexed: 02/07/2023] Open
Abstract
Background Over the last several decades, hydrogen sulfide (H2S) has been found to exert multiple physiological functions in mammal systems. The endogenous production of H2S is primarily mediated by cystathione β-synthase (CBS), cystathione γ-lyase (CSE), and 3-mercaptopyruvate sulfurtransferase (3-MST). These enzymes are widely expressed in the liver tissues and regulate hepatic functions by acting on various molecular targets. Aim of Review In the present review, we will highlight the recent advancements in the cellular events triggered by H2S under liver diseases. The therapeutic effects of H2S donors on hepatic diseases will also be discussed. Key Scientific Concepts of Review As a critical regulator of liver functions, H2S is critically involved in the etiology of various liver disorders, such as nonalcoholic steatohepatitis (NASH), hepatic fibrosis, hepatic ischemia/reperfusion (IR) injury, and liver cancer. Targeting H2S-producing enzymes may be a promising strategy for managing hepatic disorders.
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Key Words
- 3-MP, 3-mercaptopyruvate
- 3-MST, 3-mercaptopyruvate sulfurtransferase
- AGTR1, angiotensin II type 1 receptor
- AMPK, AMP-activated protein kinase
- Akt, protein kinase B
- CAT, cysteine aminotransferase
- CBS, cystathione β-synthase
- CO, carbon monoxide
- COX-2, cyclooxygenase-2
- CSE, cystathione γ-lyase
- CX3CR1, chemokine CX3C motif receptor 1
- Cancer
- DAO, D-amino acid oxidase
- DATS, Diallyl trisulfide
- EGFR, epidermal growth factor receptor
- ERK, extracellular regulated protein kinases
- FAS, fatty acid synthase
- Fibrosis
- H2S, hydrogen sulfide
- HFD, high fat diet
- HO-1, heme oxygenase 1
- Hydrogen sulfide
- IR, ischemia/reperfusion
- Liver disease
- MMP-2, matrix metalloproteinase 2
- NADH, nicotinamide adenine dinucleotide
- NADPH, nicotinamide adenine dinucleotide phosphate
- NAFLD, non-alcoholic fatty liver diseases
- NASH, nonalcoholic steatohepatitis
- NF-κB, nuclear factor-kappa B
- NaHS, sodium hydrosulfide
- Nrf2, nuclear factor erythroid2-related factor 2
- PI3K, phosphatidylinositol 3-kinase
- PLP, pyridoxal 5′-phosphate
- PPG, propargylglycine
- PTEN, phosphatase and tensin homolog deleted on chromosome ten
- SAC, S-allyl-cysteine
- SPRC, S-propargyl-cysteine
- STAT3, signal transducer and activator of transcription 3
- Steatosis
- VLDL, very low density lipoprotein
- mTOR, mammalian target of rapamycin
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Affiliation(s)
- Hai-Jian Sun
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117597, Singapore
| | - Zhi-Yuan Wu
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117597, Singapore
| | - Xiao-Wei Nie
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117597, Singapore
| | - Xin-Yu Wang
- Department of Endocrinology, The First Affiliated Hospital of Shenzhen University (Shenzhen Second People's Hospital), Shenzhen 518037, China
| | - Jin-Song Bian
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117597, Singapore.,National University of Singapore Research Institute, Suzhou 215000, China
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da Silva RP, Eudy BJ, Deminice R. One-Carbon Metabolism in Fatty Liver Disease and Fibrosis: One-Carbon to Rule Them All. J Nutr 2020; 150:994-1003. [PMID: 32119738 DOI: 10.1093/jn/nxaa032] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Revised: 11/14/2019] [Accepted: 01/30/2020] [Indexed: 02/07/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a term used to characterize a range of disease states that involve the accumulation of fat in the liver but are not associated with excessive alcohol consumption. NAFLD is a prevalent disease that can progress to organ damage like liver cirrhosis and hepatocellular carcinoma. Many animal models have demonstrated that one-carbon metabolism is strongly associated with NAFLD. Phosphatidylcholine is an important phospholipid that affects hepatic lipid homeostasis and de novo synthesis of this phospholipid is associated with NAFLD. However, one-carbon metabolism serves to support all cellular methylation reactions and catabolism of methionine, serine, glycine, choline, betaine, tryptophan, and histidine. Several different pathways within one-carbon metabolism that play important roles in regulating energy metabolism and immune function have received less attention in the study of fatty liver disease and fibrosis. This review examines what we have learned about hepatic lipid metabolism and liver damage from the study of one-carbon metabolism thus far and highlights unexplored opportunities for future research.
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Affiliation(s)
- Robin P da Silva
- Department of Food Science and Human Nutrition, University of Florida, Gainesville, FL, USA
| | - Brandon J Eudy
- Department of Food Science and Human Nutrition, University of Florida, Gainesville, FL, USA
| | - Rafael Deminice
- Department of Physical Education, State University of Londrina, Londrina, Paraná, Brazil
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Zuhra K, Augsburger F, Majtan T, Szabo C. Cystathionine-β-Synthase: Molecular Regulation and Pharmacological Inhibition. Biomolecules 2020; 10:E697. [PMID: 32365821 PMCID: PMC7277093 DOI: 10.3390/biom10050697] [Citation(s) in RCA: 146] [Impact Index Per Article: 29.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Revised: 04/24/2020] [Accepted: 04/27/2020] [Indexed: 12/11/2022] Open
Abstract
Cystathionine-β-synthase (CBS), the first (and rate-limiting) enzyme in the transsulfuration pathway, is an important mammalian enzyme in health and disease. Its biochemical functions under physiological conditions include the metabolism of homocysteine (a cytotoxic molecule and cardiovascular risk factor) and the generation of hydrogen sulfide (H2S), a gaseous biological mediator with multiple regulatory roles in the vascular, nervous, and immune system. CBS is up-regulated in several diseases, including Down syndrome and many forms of cancer; in these conditions, the preclinical data indicate that inhibition or inactivation of CBS exerts beneficial effects. This article overviews the current information on the expression, tissue distribution, physiological roles, and biochemistry of CBS, followed by a comprehensive overview of direct and indirect approaches to inhibit the enzyme. Among the small-molecule CBS inhibitors, the review highlights the specificity and selectivity problems related to many of the commonly used "CBS inhibitors" (e.g., aminooxyacetic acid) and provides a comprehensive review of their pharmacological actions under physiological conditions and in various disease models.
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Affiliation(s)
- Karim Zuhra
- Chair of Pharmacology, Section of Medicine, University of Fribourg, 1702 Fribourg, Switzerland; (K.Z.); (F.A.)
| | - Fiona Augsburger
- Chair of Pharmacology, Section of Medicine, University of Fribourg, 1702 Fribourg, Switzerland; (K.Z.); (F.A.)
| | - Tomas Majtan
- Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA;
| | - Csaba Szabo
- Chair of Pharmacology, Section of Medicine, University of Fribourg, 1702 Fribourg, Switzerland; (K.Z.); (F.A.)
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Loiselle JJ, Yang G, Wu L. Hydrogen sulfide and hepatic lipid metabolism - a critical pairing for liver health. Br J Pharmacol 2020; 177:757-768. [PMID: 30499137 PMCID: PMC7024709 DOI: 10.1111/bph.14556] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Revised: 10/22/2018] [Accepted: 10/29/2018] [Indexed: 12/13/2022] Open
Abstract
Hydrogen sulfide (H2 S) is the most recently recognized gasotransmitter, influencing a wide range of physiological processes. As a critical regulator of metabolism, H2 S has been suggested to be involved in the pathology of many diseases, particularly obesity, diabetes and cardiovascular disorders. Its involvement in liver health has been brought to light more recently, particularly through knockout animal models, which show severe hepatic lipid accumulation upon ablation of H2 S metabolic pathways. A complex relationship between H2 S and lipid metabolism in the liver is emerging, which has significant implications for liver disease establishment and/or progression, regardless of the disease-causing agent. In this review, we discuss the critical importance of H2 S in hepatic lipid metabolism. We then describe the animal models so far related with H2 S and lipid-associated liver disease, as well as H2 S-based treatments available. Finally, we highlight important considerations for future studies and identify areas in which much still remains to be determined. LINKED ARTICLES: This article is part of a themed section on Hydrogen Sulfide in Biology & Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.4/issuetoc.
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Affiliation(s)
- Julie J Loiselle
- Cardiovascular and Metabolic Research UnitLaurentian UniversitySudburyCanada
- School of Human KineticsLaurentian UniversitySudburyCanada
- Health Sciences North Research InstituteSudburyCanada
| | - Guangdong Yang
- Cardiovascular and Metabolic Research UnitLaurentian UniversitySudburyCanada
- Department of Chemistry and BiochemistryLaurentian UniversitySudburyCanada
| | - Lingyun Wu
- Cardiovascular and Metabolic Research UnitLaurentian UniversitySudburyCanada
- School of Human KineticsLaurentian UniversitySudburyCanada
- Health Sciences North Research InstituteSudburyCanada
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Dysregulated Choline, Methionine, and Aromatic Amino Acid Metabolism in Patients with Wilson Disease: Exploratory Metabolomic Profiling and Implications for Hepatic and Neurologic Phenotypes. Int J Mol Sci 2019; 20:ijms20235937. [PMID: 31779102 PMCID: PMC6928853 DOI: 10.3390/ijms20235937] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2019] [Revised: 11/22/2019] [Accepted: 11/23/2019] [Indexed: 02/07/2023] Open
Abstract
Wilson disease (WD) is a genetic copper overload condition characterized by hepatic and neuropsychiatric symptoms with a not well-understood pathogenesis. Dysregulated methionine cycle is reported in animal models of WD, though not verified in humans. Choline is essential for lipid and methionine metabolism. Defects in neurotransmitters as acetylcholine, and biogenic amines are reported in WD; however, less is known about their circulating precursors. We aimed to study choline, methionine, aromatic amino acids, and phospholipids in serum of WD subjects. Hydrophilic interaction chromatography-quadrupole time-of-flight mass spectrometry was employed to profile serum of WD subjects categorized as hepatic, neurologic, and pre-clinical. Hepatic transcript levels of genes related to choline and methionine metabolism were verified in the Jackson Laboratory toxic milk mouse model of WD (tx-j). Compared to healthy subjects, choline, methionine, ornithine, proline, phenylalanine, tyrosine, and histidine were significantly elevated in WD, with marked alterations in phosphatidylcholines and reductions in sphingosine-1-phosphate, sphingomyelins, and acylcarnitines. In tx-j mice, choline, methionine, and phosphatidylcholine were similarly dysregulated. Elevated choline is a hallmark dysregulation in WD interconnected with alterations in methionine and phospholipid metabolism, which are relevant to hepatic steatosis. The elevated phenylalanine, tyrosine, and histidine carry implications for neurologic manifestations and are worth further investigation.
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Damba T, Zhang M, Buist-Homan M, van Goor H, Faber KN, Moshage H. Hydrogen sulfide stimulates activation of hepatic stellate cells through increased cellular bio-energetics. Nitric Oxide 2019; 92:26-33. [PMID: 31401106 DOI: 10.1016/j.niox.2019.08.004] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2019] [Revised: 08/06/2019] [Accepted: 08/08/2019] [Indexed: 12/28/2022]
Abstract
Hepatic fibrosis is caused by chronic inflammation and characterized as the excessive accumulation of extracellular matrix (ECM) by activated hepatic stellate cells (HSCs). Gasotransmitters like NO and CO are known to modulate inflammation and fibrosis, however, little is known about the role of the gasotransmitter hydrogen sulfide (H2S) in liver fibrogenesis and stellate cell activation. Endogenous H2S is produced by the enzymes cystathionine β-synthase (CBS), cystathionine γ-lyase (CTH) and 3-mercaptopyruvate sulfur transferase (MPST) [1]. The aim of this study was to elucidate the role of endogenously produced and/or exogenously administered H2S on rat hepatic stellate cell activation and fibrogenesis. Primary rat HSCs were culture-activated for 7 days and treated with different H2S releasing donors (slow releasing donor GYY4137, fast releasing donor NaHS) or inhibitors of the H2S producing enzymes CTH and CBS (DL-PAG, AOAA). The main message of our study is that mRNA and protein expression level of H2S synthesizing enzymes are low in HSCs compared to hepatocytes and Kupffer cells. However, H2S promotes hepatic stellate cell activation. This conclusion is based on the fact that production of H2S and mRNA and protein expression of its producing enzyme CTH are increased during hepatic stellate cell activation. Furthermore, exogenous H2S increased HSC proliferation while inhibitors of endogenous H2S production reduce proliferation and fibrotic makers of HSCs. The effect of H2S on stellate cell activation correlated with increased cellular bioenergetics. Our results indicate that the H2S generation in hepatic stellate cells is a target for anti-fibrotic intervention and that systemic interventions with H2S should take into account cell-specific effects of H2S.
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Affiliation(s)
- Turtushikh Damba
- Dept. Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Mengfan Zhang
- Dept. Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Manon Buist-Homan
- Dept. Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; Dept. Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Harry van Goor
- Dept. Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Klaas Nico Faber
- Dept. Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; Dept. Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Han Moshage
- Dept. Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; Dept. Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
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38
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Le Stunff H, Véret J, Kassis N, Denom J, Meneyrol K, Paul JL, Cruciani-Guglielmacci C, Magnan C, Janel N. Deciphering the Link Between Hyperhomocysteinemia and Ceramide Metabolism in Alzheimer-Type Neurodegeneration. Front Neurol 2019; 10:807. [PMID: 31417486 PMCID: PMC6684947 DOI: 10.3389/fneur.2019.00807] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2019] [Accepted: 07/15/2019] [Indexed: 12/13/2022] Open
Abstract
Aging is one of the strongest risk factor for Alzheimer's disease (AD). However, several data suggest that dyslipidemia can either contribute or serve as co-factors in AD appearance. AD could be examined as a metabolic disorder mediated by peripheral insulin resistance. Insulin resistance is associated with dyslipidemia, which results in increased hepatic ceramide generation. Hepatic steatosis induces pro-inflammatory cytokine activation which is mediated by the increased ceramides production. Ceramides levels increased in cells due to perturbation in sphingolipid metabolism and upregulated expression of enzymes involved in ceramide synthesis. Cytotoxic ceramides and related molecules generated in liver promote insulin resistance, traffic through the circulation due to injury or cell death caused by local liver inflammation, and because of their hydrophobic nature, they can cross the blood-brain barrier and thereby exert neurotoxic responses as reducing insulin signaling and increasing pro-inflammatory cytokines. These abnormalities propagate a cascade of neurodegeneration associated with oxidative stress and ceramide generation, which potentiate brain insulin resistance, apoptosis, myelin degeneration, and neuro-inflammation. Therefore, excess of toxic lipids generated in liver can cause neurodegeneration. Elevated homocysteine level is also a risk factor for AD pathology and is narrowly associated with metabolic diseases and non-alcoholic fatty liver disease. The existence of a homocysteine/ceramides signaling pathway suggests that homocysteine toxicity could be partly mediated by intracellular ceramide accumulation due to stimulation of ceramide synthase. In this article, we briefly examined the role of homocysteine and ceramide metabolism linking metabolic diseases and non-alcoholic fatty liver disease to AD. We therefore analyzed the expression of mainly enzymes implicated in ceramide and sphingolipid metabolism and demonstrated deregulation of de novo ceramide biosynthesis and S1P metabolism in liver and brain of hyperhomocysteinemic mice.
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Affiliation(s)
- Hervé Le Stunff
- Université de Paris, BFA, UMR 8251, CNRS, Paris, France.,Institut des Neurosciences Paris-Saclay (Neuro-PSI), Université Paris-Sud, CNRS UMR 9197, Orsay, France
| | - Julien Véret
- Université de Paris, BFA, UMR 8251, CNRS, Paris, France
| | - Nadim Kassis
- Université de Paris, BFA, UMR 8251, CNRS, Paris, France
| | - Jessica Denom
- Université de Paris, BFA, UMR 8251, CNRS, Paris, France
| | | | - Jean-Louis Paul
- AP-HP, Hôpital Européen Georges Pompidou, Service de Biochimie, Paris, France
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Kar S, Shahshahan HR, Kambis TN, Yadav SK, Li Z, Lefer DJ, Mishra PK. Hydrogen Sulfide Ameliorates Homocysteine-Induced Cardiac Remodeling and Dysfunction. Front Physiol 2019; 10:598. [PMID: 31178749 PMCID: PMC6544124 DOI: 10.3389/fphys.2019.00598] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Accepted: 04/26/2019] [Indexed: 12/13/2022] Open
Abstract
Patients with diabetes, a methionine-rich meat diet, or certain genetic polymorphisms show elevated levels of homocysteine (Hcy), which is strongly associated with the development of cardiovascular disease including diabetic cardiomyopathy. However, reducing Hcy levels with folate shows no beneficial cardiac effects. We have previously shown that a hydrogen sulfide (H2S), a by-product of Hcy through transsulfuration by cystathionine beta synthase (CBS), donor mitigates Hcy-induced hypertrophy in cardiomyocytes. However, the in vivo cardiac effects of H2S in the context of hyperhomocysteinemia (HHcy) have not been studied. We tested the hypothesis that HHcy causes cardiac remodeling and dysfunction in vivo, which is ameliorated by H2S. Twelve-week-old male CBS+/− (a model of HHcy) and sibling CBS+/+ (WT) mice were treated with SG1002 (a slow release H2S donor) diet for 4 months. The left ventricle of CBS+/− mice showed increased expression of early remodeling signals c-Jun and c-Fos, increased interstitial collagen deposition, and increased cellular hypertrophy. Notably, SG1002 treatment slightly reduced c-Jun and c-Fos expression, decreased interstitial fibrosis, and reduced cellular hypertrophy. Pressure volume loop analyses in CBS+/− mice revealed increased end systolic pressure with no change in stroke volume (SV) suggesting increased afterload, which was abolished by SG1002 treatment. Additionally, SG1002 treatment increased end-diastolic volume and SV in CBS+/− mice, suggesting increased ventricular filling. These results demonstrate SG1002 treatment alleviates cardiac remodeling and afterload in HHcy mice. H2S may be cardioprotective in conditions where H2S is reduced and Hcy is elevated.
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Affiliation(s)
- Sumit Kar
- Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NE, United States
| | - Hamid R Shahshahan
- Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NE, United States
| | - Tyler N Kambis
- Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NE, United States
| | - Santosh K Yadav
- Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NE, United States
| | - Zhen Li
- Department of Pharmacology and Experimental Therapeutics, Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA, United States
| | - David J Lefer
- Department of Pharmacology and Experimental Therapeutics, Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA, United States
| | - Paras K Mishra
- Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NE, United States.,Department of Anesthesiology, University of Nebraska Medical Center, Omaha, NE, United States
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Heo G, Ko KS. Long-Term Feeding of Soy Protein Attenuates Choline Deficient-Induced Adverse Effects in Wild Type Mice and Prohibitin 1 Deficient Mice Response More Sensitively. Prev Nutr Food Sci 2019; 24:32-40. [PMID: 31008094 PMCID: PMC6456240 DOI: 10.3746/pnf.2019.24.1.32] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2018] [Accepted: 01/31/2019] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, however the exact cause of NAFLD remains unknown. Methionine, an essential amino acid, is the first limiting amino acid of soy protein, and its deficiency is suggested to cause hepatocyte damage and NAFLD. The objective of this study is to examine the changes in NAFLD susceptibility with soy protein consumption and deterioration due to prohibitin 1 (PHB1) deficiency, an important protein in hepatic mitochondrial function. In this study, liver-specific phb1 +/- mice and wild-type mice were fed a normal diet, choline-deficient diet (CDD), or soy protein diet without choline (SPD) for 16 weeks. Using hematoxylin and eosin staining, we showed that SPD attenuates symptoms of hepatocyte damage and lipid accumulation induced by CDD in mouse liver. The liver damage in mice fed the SPD was alleviated by decreasing lipogenic markers and by increasing anti-inflammatory markers. Furthermore, mRNA expression of genes involved in hepatic methionine metabolism was significantly lower in liver-specific phb1 +/- mice fed with a SPD compared with wild-type mice fed with a SPD. These data suggest a CDD can cause non-alcohol related liver damage, which can be attenuated by a SPD in wild-type mice. These phenomena were not observed in liver-specific phb1 +/- mice. It may therefore be concluded that SPD attenuates CDD-induced liver damage in wild-type mice, and that PHB1 deficiency blocks the beneficial effects of SPD against CDD-induced liver damage.
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Affiliation(s)
- Gieun Heo
- Department of Nutritional Science and Food Management, Ewha Womans University, Seoul 03760, Korea
| | - Kwang Suk Ko
- Department of Nutritional Science and Food Management, Ewha Womans University, Seoul 03760, Korea
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Yao L, Cao B, Cheng Q, Cai W, Ye C, Liang J, Liu W, Tan L, Yan M, Li B, He J, Hwang SH, Zhang X, Wang C, Ai D, Hammock BD, Zhu Y. Inhibition of soluble epoxide hydrolase ameliorates hyperhomocysteinemia-induced hepatic steatosis by enhancing β-oxidation of fatty acid in mice. Am J Physiol Gastrointest Liver Physiol 2019; 316:G527-G538. [PMID: 30789748 PMCID: PMC6483021 DOI: 10.1152/ajpgi.00148.2018] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Hepatic steatosis is the beginning phase of nonalcoholic fatty liver disease, and hyperhomocysteinemia (HHcy) is a significant risk factor. Soluble epoxide hydrolase (sEH) hydrolyzes epoxyeicosatrienoic acids (EETs) and other epoxy fatty acids, attenuating their cardiovascular protective effects. However, the involvement of sEH in HHcy-induced hepatic steatosis is unknown. The current study aimed to explore the role of sEH in HHcy-induced lipid disorder. We fed 6-wk-old male mice a chow diet or 2% (wt/wt) high-metnionine diet for 8 wk to establish the HHcy model. A high level of homocysteine induced lipid accumulation in vivo and in vitro, which was concomitant with the increased activity and expression of sEH. Treatment with a highly selective specific sEH inhibitor (0.8 mg·kg-1·day-1 for the animal model and 1 μM for cells) prevented HHcy-induced lipid accumulation in vivo and in vitro. Inhibition of sEH activated the peroxisome proliferator-activated receptor-α (PPAR-α), as evidenced by elevated β-oxidation of fatty acids and the expression of PPAR-α target genes in HHcy-induced hepatic steatosis. In primary cultured hepatocytes, the effect of sEH inhibition on PPAR-α activation was further confirmed by a marked increase in PPAR-response element luciferase activity, which was reversed by knock down of PPAR-α. Of note, 11,12-EET ligand dependently activated PPAR-α. Thus increased sEH activity is a key determinant in the pathogenesis of HHcy-induced hepatic steatosis, and sEH inhibition could be an effective treatment for HHcy-induced hepatic steatosis. NEW & NOTEWORTHY In the current study, we demonstrated that upregulation of soluble epoxide hydrolase (sEH) is involved in the hyperhomocysteinemia (HHcy)-caused hepatic steatosis in an HHcy mouse model and in murine primary hepatocytes. Improving hepatic steatosis in HHcy mice by pharmacological inhibition of sEH to activate peroxisome proliferator-activated receptor-α was ligand dependent, and sEH could be a potential therapeutic target for the treatment of nonalcoholic fatty liver disease.
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Affiliation(s)
- Liu Yao
- 1Tianjin Key Laboratory of Metabolic Diseases; Key Laboratory of Immune Microenvironment and Disease (Ministry of Education); Collaborative Innovation Center of Tianjin for Medical Epigenetics and Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China
| | - Boyang Cao
- 1Tianjin Key Laboratory of Metabolic Diseases; Key Laboratory of Immune Microenvironment and Disease (Ministry of Education); Collaborative Innovation Center of Tianjin for Medical Epigenetics and Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China
| | - Qian Cheng
- 1Tianjin Key Laboratory of Metabolic Diseases; Key Laboratory of Immune Microenvironment and Disease (Ministry of Education); Collaborative Innovation Center of Tianjin for Medical Epigenetics and Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China
| | - Wenbin Cai
- 1Tianjin Key Laboratory of Metabolic Diseases; Key Laboratory of Immune Microenvironment and Disease (Ministry of Education); Collaborative Innovation Center of Tianjin for Medical Epigenetics and Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China
| | - Chenji Ye
- 1Tianjin Key Laboratory of Metabolic Diseases; Key Laboratory of Immune Microenvironment and Disease (Ministry of Education); Collaborative Innovation Center of Tianjin for Medical Epigenetics and Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China
| | - Jing Liang
- 1Tianjin Key Laboratory of Metabolic Diseases; Key Laboratory of Immune Microenvironment and Disease (Ministry of Education); Collaborative Innovation Center of Tianjin for Medical Epigenetics and Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China
| | - Wenli Liu
- 1Tianjin Key Laboratory of Metabolic Diseases; Key Laboratory of Immune Microenvironment and Disease (Ministry of Education); Collaborative Innovation Center of Tianjin for Medical Epigenetics and Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China
| | - Lu Tan
- 2Department of Laboratory Animal Science and Technology, Tianjin Medical University, Tianjin, China
| | - Meng Yan
- 1Tianjin Key Laboratory of Metabolic Diseases; Key Laboratory of Immune Microenvironment and Disease (Ministry of Education); Collaborative Innovation Center of Tianjin for Medical Epigenetics and Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China
| | - Bochuan Li
- 1Tianjin Key Laboratory of Metabolic Diseases; Key Laboratory of Immune Microenvironment and Disease (Ministry of Education); Collaborative Innovation Center of Tianjin for Medical Epigenetics and Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China
| | - Jinlong He
- 1Tianjin Key Laboratory of Metabolic Diseases; Key Laboratory of Immune Microenvironment and Disease (Ministry of Education); Collaborative Innovation Center of Tianjin for Medical Epigenetics and Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China
| | - Sung Hee Hwang
- 3Department of Entomology and Nematology and University of California, Davis Comprehensive Cancer Center, Davis, California
| | - Xu Zhang
- 1Tianjin Key Laboratory of Metabolic Diseases; Key Laboratory of Immune Microenvironment and Disease (Ministry of Education); Collaborative Innovation Center of Tianjin for Medical Epigenetics and Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China
| | - Chunjiong Wang
- 1Tianjin Key Laboratory of Metabolic Diseases; Key Laboratory of Immune Microenvironment and Disease (Ministry of Education); Collaborative Innovation Center of Tianjin for Medical Epigenetics and Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China
| | - Ding Ai
- 1Tianjin Key Laboratory of Metabolic Diseases; Key Laboratory of Immune Microenvironment and Disease (Ministry of Education); Collaborative Innovation Center of Tianjin for Medical Epigenetics and Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China
| | - Bruce D. Hammock
- 3Department of Entomology and Nematology and University of California, Davis Comprehensive Cancer Center, Davis, California
| | - Yi Zhu
- 1Tianjin Key Laboratory of Metabolic Diseases; Key Laboratory of Immune Microenvironment and Disease (Ministry of Education); Collaborative Innovation Center of Tianjin for Medical Epigenetics and Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China
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Minami S, Miura K, Ishioka M, Morimoto N, Isoda N, Yamamoto H, Iijima K. Homocysteine supplementation ameliorates steatohepatitis induced by a choline-deficient diet in mice. Hepatol Res 2019; 49:189-200. [PMID: 30048033 DOI: 10.1111/hepr.13234] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2018] [Revised: 07/11/2018] [Accepted: 07/17/2018] [Indexed: 01/18/2023]
Abstract
AIM High concentrations of homocysteine are believed to induce lipid synthesis and cell injury through endoplasmic reticulum (ER) stress in metabolic syndrome. However, homocysteine could be used to improve steatohepatitis induced by choline deficiency, in which methyl donors are decreased. The aim of the present study was to clarify the role of the physiological concentration of homocysteine in the development of steatohepatitis induced by choline deficiency. METHODS Wild-type mice were fed a choline-deficient amino acid-defined (CDAA) diet with or without homocysteine supplementation for 24 weeks. Liver cells isolated from mice were exposed to homocysteine under choline-deficient conditions. RESULTS Wild-type mice fed the CDAA diet developed steatohepatitis with increased ER stress and decreased S-adenosylmethionine (SAM), a methyl donor. Homocysteine supplementation reduced ER stress and restored hepatic SAM, leading to the improvement of steatohepatitis. In in vitro experiments using primary cultured hepatocytes, the physiological concentration of homocysteine decreased the lipid accumulation and ER stress induced by the choline-deficient conditions. However, hepatocyte death was not induced by a physiological concentration of homocysteine or in choline-deficient medium. Interestingly, tumor necrosis factor (TNF)α promoted hepatocyte death under choline-deficient conditions, which was suppressed by homocysteine supplementation. Hepatic macrophages increased the production of TNFα under choline-deficient conditions whereas supplementation of SAM reduced the TNFα production. CONCLUSIONS Homocysteine supplementation ameliorates steatohepatitis by reducing ER stress and increasing SAM in mice fed a CDAA diet. These results were opposite to those of previous reports, which showed that homocysteine induced cell injury.
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Affiliation(s)
- Shinichiro Minami
- Department of Gastroenterology, Akita University Graduate School of Medicine, Akita, Japan
| | - Kouichi Miura
- Department of Gastroenterology, Akita University Graduate School of Medicine, Akita, Japan.,Division of Gastroenterology, Department of Medicine, Jichi Medical University School of Medicine, Shimotsuke, Japan
| | - Mitsuaki Ishioka
- Department of Gastroenterology, Akita University Graduate School of Medicine, Akita, Japan
| | - Naoki Morimoto
- Division of Gastroenterology, Department of Medicine, Jichi Medical University School of Medicine, Shimotsuke, Japan
| | - Norio Isoda
- Division of Gastroenterology, Department of Medicine, Jichi Medical University School of Medicine, Shimotsuke, Japan
| | - Hironori Yamamoto
- Division of Gastroenterology, Department of Medicine, Jichi Medical University School of Medicine, Shimotsuke, Japan
| | - Katsunori Iijima
- Department of Gastroenterology, Akita University Graduate School of Medicine, Akita, Japan
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Hydrogen Sulfide as a Novel Regulatory Factor in Liver Health and Disease. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:3831713. [PMID: 30805080 PMCID: PMC6360590 DOI: 10.1155/2019/3831713] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/25/2018] [Accepted: 11/29/2018] [Indexed: 02/08/2023]
Abstract
Hydrogen sulfide (H2S), a colorless gas smelling of rotten egg, has long been recognized as a toxic gas and environment pollutant. However, increasing evidence suggests that H2S acts as a novel gasotransmitter and plays important roles in a variety of physiological and pathological processes in mammals. H2S is involved in many hepatic functions, including the regulation of oxidative stress, glucose and lipid metabolism, vasculature, mitochondrial function, differentiation, and circadian rhythm. In addition, H2S contributes to the pathogenesis and treatment of a number of liver diseases, such as hepatic fibrosis, liver cirrhosis, liver cancer, hepatic ischemia/reperfusion injury, nonalcoholic fatty liver disease/nonalcoholic steatohepatitis, hepatotoxicity, and acute liver failure. In this review, the biosynthesis and metabolism of H2S in the liver are summarized and the role and mechanism of H2S in liver health and disease are further discussed.
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Li M, Xu C, Shi J, Ding J, Wan X, Chen D, Gao J, Li C, Zhang J, Lin Y, Tu Z, Kong X, Li Y, Yu C. Fatty acids promote fatty liver disease via the dysregulation of 3-mercaptopyruvate sulfurtransferase/hydrogen sulfide pathway. Gut 2018; 67:2169-2180. [PMID: 28877979 PMCID: PMC6241611 DOI: 10.1136/gutjnl-2017-313778] [Citation(s) in RCA: 122] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2017] [Revised: 07/14/2017] [Accepted: 08/21/2017] [Indexed: 02/07/2023]
Abstract
OBJECTIVE Accumulation of free fatty acids (FFAs) in hepatocytes induces lipotoxicity, leading to non-alcoholic fatty liver disease (NAFLD). This study aimed to investigate the underlying mechanisms by which FFA contributes to the pathogenesis of NAFLD via the regulation of 3-mercaptopyruvate sulfurtransferase (MPST), a key enzyme that regulates endogenous hydrogen sulfide (H2S) biosynthesis. DESIGN Hepatic MPST expression was evaluated in mice and patients with NAFLD. A variety of molecular approaches were used to study the effects of MPST regulation on hepatic steatosis in vivo and in vitro. RESULTS In vitro treatment of hepatocytes with FFAs upregulated MPST expression, which was partially dependent on NF-κB/p65. Hepatic MPST expression was markedly increased in high fat diet (HFD)-fed mice and patients with NAFLD. Partial knockdown of MPST via adenovirus delivery of MPST short hairpin RNA or heterozygous deletion of the Mpst gene significantly ameliorated hepatic steatosis in HFD-fed mice. Consistently, inhibition of MPST also reduced FFA-induced fat accumulation in L02 cells. Intriguingly, inhibition of MPST significantly enhanced rather than decreased H2S production, whereas MPST overexpression markedly inhibited H2S production. Co-immunoprecipitation experiments showed that MPST directly interacted with and negatively regulated cystathionine γ-lyase (CSE), a major source of H2S production in the liver. Mechanistically, MPST promoted steatosis via inhibition of CSE/H2S and subsequent upregulation of the sterol regulatory element-binding protein 1c pathway, C-Jun N-terminal kinase phosphorylation and hepatic oxidative stress. CONCLUSIONS FFAs upregulate hepatic expression of MPST and subsequently inhibit the CSE/H2S pathway, leading to NAFLD. MPST may be a potential therapeutic target for NAFLD.
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Affiliation(s)
- Meng Li
- Department of Gastroenterology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Chengfu Xu
- Department of Gastroenterology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Junping Shi
- Division of Hepatology, Hangzhou Normal University Affiliated Hospital, Hangzhou, Zhejiang, China
| | - Jiexia Ding
- Department of Gastroenterology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Xingyong Wan
- Department of Gastroenterology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Dahua Chen
- Department of Gastroenterology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Jianguo Gao
- Department of Gastroenterology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Chunxiao Li
- Department of Gastroenterology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Jie Zhang
- Department of Gastroenterology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Yiming Lin
- Department of Gastroenterology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Zhenhua Tu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Xiaoni Kong
- Department of Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Youming Li
- Department of Gastroenterology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Chaohui Yu
- Department of Gastroenterology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
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Cruciani-Guglielmacci C, Meneyrol K, Migrenne-Li S, Denom J, Daubigney F, Le Stunff H, Ibberson M, Thorens B, Janel N, Magnan C. Les souris déficientes en Cystathionine Beta Synthase et supplémentées en méthionine présentent un défaut de sécrétion d’insuline associé à une moindre prise de poids et une hypersensibilité à l’insuline. NUTR CLIN METAB 2018. [DOI: 10.1016/j.nupar.2018.09.091] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
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A pharmacological probe identifies cystathionine β-synthase as a new negative regulator for ferroptosis. Cell Death Dis 2018; 9:1005. [PMID: 30258181 PMCID: PMC6158189 DOI: 10.1038/s41419-018-1063-2] [Citation(s) in RCA: 99] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2018] [Revised: 07/26/2018] [Accepted: 08/30/2018] [Indexed: 12/16/2022]
Abstract
Cystathionine β-synthase (CBS) is responsible for the first enzymatic reaction in the transsulfuration pathway of sulfur amino acids. The molecular function and mechanism of CBS as well as that of transsulfuration pathway remain ill-defined in cell proliferation and death. In the present study, we designed, synthesized and obtained a bioactive inhibitor CH004 for human CBS, which functions in vitro and in vivo. CH004 inhibits CBS activity, elevated the cellular homocysteine and suppressed the production of hydrogen sulfide in a dose-dependent manner in cells or in vivo. Chemical or genetic inhibition of CBS demonstrates that endogenous CBS is closely coupled with cell proliferation and cell cycle. Moreover, CH004 substantially retarded in vivo tumor growth in a xenograft mice model of liver cancer. Importantly, inhibition of CBS triggers ferroptosis in hepatocellular carcinoma. Overall, the study provides several clues for studying the interplays amongst transsulfuration pathway, ferroptosis and liver cancer.
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Cystathionine β-Synthase in Physiology and Cancer. BIOMED RESEARCH INTERNATIONAL 2018; 2018:3205125. [PMID: 30050925 PMCID: PMC6046153 DOI: 10.1155/2018/3205125] [Citation(s) in RCA: 80] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/23/2018] [Accepted: 05/29/2018] [Indexed: 01/20/2023]
Abstract
Cystathionine β-synthase (CBS) regulates homocysteine metabolism and contributes to hydrogen sulfide (H2S) biosynthesis through which it plays multifunctional roles in the regulation of cellular energetics, redox status, DNA methylation, and protein modification. Inactivating mutations in CBS contribute to the pathogenesis of the autosomal recessive disease CBS-deficient homocystinuria. Recent studies demonstrating that CBS promotes colon and ovarian cancer growth in preclinical models highlight a newly identified oncogenic role for CBS. On the contrary, tumor-suppressive effects of CBS have been reported in other cancer types, suggesting context-dependent roles of CBS in tumor growth and progression. Here, we review the physiological functions of CBS, summarize the complexities regarding CBS research in oncology, and discuss the potential of CBS and its key metabolites, including homocysteine and H2S, as potential biomarkers for cancer diagnosis or therapeutic targets for cancer treatment.
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Ibrahim S, Maqbool S, Azam M, Iqbal MP, Qamar R. CBS mutations and MTFHR SNPs causative of hyperhomocysteinemia in Pakistani children. Mol Biol Rep 2018; 45:353-360. [PMID: 29600437 DOI: 10.1007/s11033-018-4169-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2016] [Accepted: 03/24/2018] [Indexed: 11/26/2022]
Abstract
Three index patients with hyperhomocysteinemia and ocular anomalies were screened for cystathionine beta synthase (CBS) and methylenetetrahydrofolate reductase (MTHFR) polymorphisms. Genotyping of hyperhomocysteinemia associated MTHFR polymorphisms C677T (rs1801133) and A1298C (rs1801131) was done by PCR-restriction fragment length polymorphism. Sanger sequencing was performed for CBS exonic sequences along with consensus splice sites. In the case of MTHFR polymorphisms, all the patients were heterozygous CT for the single nucleotide polymorphism (SNP) C677T and were therefore carriers of the risk allele (T), while the patients were homozygous CC for the risk genotype of the SNP A1298C. CBS sequencing resulted in the identification of two novel mutations, a missense change (c.467T>C; p.Leu156Pro) in exon 7 and an in-frame deletion (c.808_810del; p.Glu270del) in exon 10. In addition, a recurrent missense mutation (c.770C>T; p.Thr257Met) in exon 10 of the gene was also identified. The mutations were present homozygously in the patients and were inherited from the carrier parents. This is the first report from Pakistan where novel as well as recurrent CBS mutations causing hyperhomocysteinemia and lens dislocation in three patients from different families are being reported with the predicted effect of the risk allele of the MTHFR SNP in causing hyperhomocysteinemia.
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Affiliation(s)
- Shahnaz Ibrahim
- Department of Pediatrics and Child Health, Aga Khan University, Karachi, Pakistan
| | - Saadia Maqbool
- COMSATS Institute of Information Technology, Park Road, Tarlai Kalan, Islamabad, 45600, Pakistan
| | - Maleeha Azam
- COMSATS Institute of Information Technology, Park Road, Tarlai Kalan, Islamabad, 45600, Pakistan
| | - Mohammad Perwaiz Iqbal
- Department of Biological and Biomedical Sciences, Aga Khan University, Karachi, Pakistan
- Pakistan Academy of Sciences, Islamabad, Pakistan
| | - Raheel Qamar
- COMSATS Institute of Information Technology, Park Road, Tarlai Kalan, Islamabad, 45600, Pakistan.
- Pakistan Academy of Sciences, Islamabad, Pakistan.
- Al-Nafees Medical College & Hospital, Isra University, Islamabad, Pakistan.
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Altered Redox Homeostasis in Branched-Chain Amino Acid Disorders, Organic Acidurias, and Homocystinuria. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2018; 2018:1246069. [PMID: 29743968 PMCID: PMC5884027 DOI: 10.1155/2018/1246069] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/29/2017] [Revised: 12/26/2017] [Accepted: 01/16/2018] [Indexed: 02/06/2023]
Abstract
Inborn errors of metabolism (IEMs) are a group of monogenic disorders characterized by dysregulation of the metabolic networks that underlie development and homeostasis. Emerging evidence points to oxidative stress and mitochondrial dysfunction as major contributors to the multiorgan alterations observed in several IEMs. The accumulation of toxic metabolites in organic acidurias, respiratory chain, and fatty acid oxidation disorders inhibits mitochondrial enzymes and processes resulting in elevated levels of reactive oxygen species (ROS). In other IEMs, as in homocystinuria, different sources of ROS have been proposed. In patients' samples, as well as in cellular and animal models, several studies have identified significant increases in ROS levels along with decreases in antioxidant defences, correlating with oxidative damage to proteins, lipids, and DNA. Elevated ROS disturb redox-signaling pathways regulating biological processes such as cell growth, differentiation, or cell death; however, there are few studies investigating these processes in IEMs. In this review, we describe the published data on mitochondrial dysfunction, oxidative stress, and impaired redox signaling in branched-chain amino acid disorders, other organic acidurias, and homocystinuria, along with recent studies exploring the efficiency of antioxidants and mitochondria-targeted therapies as therapeutic compounds in these diseases.
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50
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Quaglia A, Roberts EA, Torbenson M. Developmental and Inherited Liver Disease. MACSWEEN'S PATHOLOGY OF THE LIVER 2018:111-274. [DOI: 10.1016/b978-0-7020-6697-9.00003-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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