|
1
|
Jin J, Meng T, Yu Y, Wu S, Jiao CC, Song S, Li YX, Zhang Y, Zhao YY, Li X, Wang Z, Liu YF, Huang R, Qin J, Chen Y, Cao H, Tan X, Ge X, Jiang C, Xue J, Yuan J, Wu D, Wu W, Jiang CZ, Wang P. Human HDAC6 senses valine abundancy to regulate DNA damage. Nature 2025; 637:215-223. [PMID: 39567688 DOI: 10.1038/s41586-024-08248-5] [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: 01/18/2022] [Accepted: 10/17/2024] [Indexed: 11/22/2024]
Abstract
As an essential branched amino acid, valine is pivotal for protein synthesis, neurological behaviour, haematopoiesis and leukaemia progression1-3. However, the mechanism by which cellular valine abundancy is sensed for subsequent cellular functions remains undefined. Here we identify that human histone deacetylase 6 (HDAC6) serves as a valine sensor by directly binding valine through a primate-specific SE14 repeat domain. The nucleus and cytoplasm shuttling of human, but not mouse, HDAC6 is tightly controlled by the intracellular levels of valine. Valine deprivation leads to HDAC6 retention in the nucleus and induces DNA damage. Mechanistically, nuclear-localized HDAC6 binds and deacetylates ten-eleven translocation 2 (TET2) to initiate active DNA demethylation, which promotes DNA damage through thymine DNA glycosylase-driven excision. Dietary valine restriction inhibits tumour growth in xenograft and patient-derived xenograft models, and enhances the therapeutic efficacy of PARP inhibitors. Collectively, our study identifies human HDAC6 as a valine sensor that mediates active DNA demethylation and DNA damage in response to valine deprivation, and highlights the potential of dietary valine restriction for cancer treatment.
Collapse
Affiliation(s)
- Jiali Jin
- Tongji University Cancer Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Tong Meng
- Tongji University Cancer Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China
- Department of Orthopedics, Shanghai General Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Yuanyuan Yu
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopaedic Department of Tongji Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Shuheng Wu
- Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China
| | - Chen-Chen Jiao
- Tongji University Cancer Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Sihui Song
- Tongji University Cancer Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Ya-Xu Li
- Tongji University Cancer Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Yu Zhang
- Tongji University Cancer Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Yuan-Yuan Zhao
- Tongji University Cancer Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Xinran Li
- Tongji University Cancer Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Zixin Wang
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Tongji Hospital affiliated to Tongji University, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Yu-Fan Liu
- Tongji University Cancer Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Runzhi Huang
- Tongji University Cancer Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Jieling Qin
- Tongji University Cancer Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Yihua Chen
- Shanghai Key Laboratory of Regulatory Biology, East China Normal University, Shanghai, China
- School of Pharmaceutical Sciences and Yunnan Key Laboratory of Pharmacology for Natural Products and Yunnan College of Modern Biomedical Industry, Kunming Medical University, Kunming, China
| | - Hao Cao
- School of Life Science and Bio-Pharmaceutics, Shenyang Pharmaceutical University, Shenyang, China
| | - Xiao Tan
- Tongji University Cancer Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Xin Ge
- Tongji University Cancer Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Cong Jiang
- Tongji University Cancer Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Jianhuang Xue
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Tongji Hospital affiliated to Tongji University, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Jian Yuan
- Department of Biochemistry and Molecular Biology, Tongji University School of Medicine, Shanghai, China
| | - Dianqing Wu
- Department of Pharmacology, Yale School of Medicine, New Haven, CT, USA
| | - Wei Wu
- Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China
| | - Ci-Zhong Jiang
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopaedic Department of Tongji Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Ping Wang
- Tongji University Cancer Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China.
| |
Collapse
|
|
2
|
Garcia MB, Thandapani P. Nutritional intervention as adjuvant therapy for T-cell acute lymphoblastic leukemia. Blood Adv 2024; 8:5266-5267. [PMID: 39093954 PMCID: PMC11492464 DOI: 10.1182/bloodadvances.2024013607] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Revised: 07/22/2024] [Accepted: 07/24/2024] [Indexed: 08/04/2024] Open
Affiliation(s)
- Miriam B. Garcia
- Department of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Palaniraja Thandapani
- Department of Hematopoietic Biology and Malignancy, The University of Texas MD Anderson Cancer Center, Houston, TX
| |
Collapse
|
|
3
|
Basta AH, Lotfy VF, Ghaly NS, Nabil M, Mohamed KM. Bioactivity evaluation of amino acid-conjugates with protein versus cellulose based conjugates and extracted flavonoids. J Drug Deliv Sci Technol 2020. [DOI: 10.1016/j.jddst.2020.101924] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
|
|
4
|
Gao G, Yao Y, Li K, Mashausi DS, Li D, Negi H, Kamle S, Chen H, Wu Z, Zhou H, Li D. A human leucyl-tRNA synthetase as an anticancer target. Onco Targets Ther 2015; 8:2933-42. [PMID: 26508878 PMCID: PMC4610879 DOI: 10.2147/ott.s88873] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Several aminoacyl-tRNA synthetases have been reported to be overexpressed for charging essential aminoacyl-tRNAs in many cancer types. In this study, we aimed to explore the potential role of leucyl-tRNA synthetase (LARS) as an anticancer target. MTT assay was performed to screen inhibitors to human LARS (hsLARS) from compounds AN2690 and its derivatives, compounds 1–6, in U2OS and SKOV3 cells. The compound with the strongest inhibitory ability was further investigated for its inhibitory effect in cancer cell lines and in an animal tumor model. Additionally, a LARS-rescue experiment was performed to explore the potential target in U2OS using Western blot and flow cytometry. Luciferase reporter assay was designed to analyze the effect of of hsLARS inhibitor on p21 activation. We identified an hsLARS inhibitor (compound 2) that suppressed the proliferation of U2OS and SKOV3 cells in vitro. A LARS-rescue experiment demonstrated that the proliferation inhibition was induced by targeting intracellular LARS. In addition, the hsLARS inhibition was shown to activate the p21 early transcription and promote cell apoptosis, as well as reduce implanted EMT6 tumor progression in mice. Our results suggest that LARS might serve as a potential anticancer target through the p21 signaling pathway and that the nutritional signaling pathway may provide a valuable anticancer strategy for further investigation.
Collapse
Affiliation(s)
- Guangwei Gao
- School of Pharmacy, Shanghai Jiao Tong University, Shanghai, People's Republic of China
| | - Ying Yao
- School of Pharmacy, Shanghai Jiao Tong University, Shanghai, People's Republic of China
| | - Kun Li
- School of Pharmacy, Shanghai Jiao Tong University, Shanghai, People's Republic of China
| | | | - Dongsheng Li
- School of Pharmacy, Shanghai Jiao Tong University, Shanghai, People's Republic of China
| | - Hema Negi
- School of Pharmacy, Shanghai Jiao Tong University, Shanghai, People's Republic of China
| | - Suchitra Kamle
- School of Pharmacy, Shanghai Jiao Tong University, Shanghai, People's Republic of China
| | - Hao Chen
- School of Pharmacy, Shanghai Jiao Tong University, Shanghai, People's Republic of China
| | - Zhenghua Wu
- School of Pharmacy, Shanghai Jiao Tong University, Shanghai, People's Republic of China
| | - Huchen Zhou
- School of Pharmacy, Shanghai Jiao Tong University, Shanghai, People's Republic of China
| | - Dawei Li
- School of Pharmacy, Shanghai Jiao Tong University, Shanghai, People's Republic of China
| |
Collapse
|
|
5
|
Wang XY, He ZC, Song LY, Spencer S, Yang LX, Peng F, Liu GM, Hu MH, Li HB, Wu XM, Zeng S, Hilgenfeld R, Stöckigt J, Zhao Y, Qian JF. Chemotherapeutic effects of bioassay-guided extracts of the American cockroach, Periplaneta americana. Integr Cancer Ther 2011; 10:NP12-23. [PMID: 21733985 DOI: 10.1177/1534735411413467] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
The organic extract of Periplaneta americana L. (Dictyoptera; Blattidae) has been traditionally used in southwestern China as an alternative medicine against disorders such as hepatitis, trauma, gastric ulcers, burns, and heart disease. The present study describes bioassay-guided purification and chemotherapeutic evaluation of the 60% ethanolic fraction of P americana organic extracts (PAE60). The most effective cytotoxic fraction was determined by way of repeated in vitro screenings against 12 distinct cultured human carcinoma cell lines: Eca 109, BGC823, HO8910, LS174T, CNE, HeLa, K562, PC-3, A549, BEL 7404, HL-60, and KB, followed by in vivo antitumor assays of the lead fraction (PAE60). The complexity of enriched active fraction was qualitatively evaluated using thin layer chromatography. Reconstituted PAE60 was effective at inhibiting HL-60, KB, CNE, and BGC823 cell growth with IC(50) values <20 µg mL-(1). PAE60 reduced tumor growth in S180-bearing immunocompetent mice by 72.62% after 10 days following oral doses of 500 mg kg d-(1) compared with 78.75% inhibition following 40 mg kg d-(1) of cyclophosphamide (CTX). Thymus and spleen indices of S180-bearing mice treated with PAE60 were significantly greater (P < .05) than CTX treatment groups, suggesting potential immunomodulation of antitumor host defenses by PAE60. Antiviral activity was also investigated and PAE60 inhibited herpes simplex type-2 replication (IC(50) = 4.11 ± 0.64 µg mL-(1)) with a selectivity index (CC(50) to IC(50) ratio) of 64.84 in Vero cells but was less effective on type-1 virus (IC(50) of 25.6 ± 3.16 µg mL-(1)). These results support future clinical trials on P. americana as an alternative or complementary medicinal agent.
Collapse
|
|
6
|
Xue R, Lin Z, Deng C, Dong L, Liu T, Wang J, Shen X. A serum metabolomic investigation on hepatocellular carcinoma patients by chemical derivatization followed by gas chromatography/mass spectrometry. RAPID COMMUNICATIONS IN MASS SPECTROMETRY : RCM 2008; 22:3061-3068. [PMID: 18767022 DOI: 10.1002/rcm.3708] [Citation(s) in RCA: 69] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/26/2023]
Abstract
The purpose of this study was to investigate the serum metabolic difference between hepatocellular carcinoma (HCC, n = 20) male patients and normal male subjects (n = 20). Serum metabolome was detected through chemical derivatization followed by gas chromatography/mass spectrometry (GC/MS). The acquired GC/MS data was analyzed by stepwise discriminant analysis (SDA) and support vector machine (SVM). The metabolites including butanoic acid, ethanimidic acid, glycerol, L-isoleucine, L-valine, aminomalonic acid, D-erythrose, hexadecanoic acid, octadecanoic acid, and 9,12-octadecadienoic acid in combination with each other gave the strongest segregation between the two groups. By applying these variables, our method provided a diagnostic model that could well discriminate between HCC patients and normal subjects. More importantly, the error count estimate for each group was 0%. The total classifying accuracy of the discriminant function tested by SVM 20-fold cross validation was 75%. This technique is different from traditional ones and appears to be a useful tool in the area of HCC diagnosis.
Collapse
Affiliation(s)
- Ruyi Xue
- Zhongshan Hospital, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | | | | | | | | | | | | |
Collapse
|
|
7
|
Djokić D, Janković D. Biological evaluation and comparison of three different procedures for labelling of amino acids tyrosine and lysine with technetium-99m. J Labelled Comp Radiopharm 2007. [DOI: 10.1002/jlcr.1205] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
|
|
8
|
Baracos VE, Mackenzie ML. Investigations of branched-chain amino acids and their metabolites in animal models of cancer. J Nutr 2006; 136:237S-42S. [PMID: 16365090 DOI: 10.1093/jn/136.1.237s] [Citation(s) in RCA: 74] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Many of the features of BCAA metabolism in the tumor-bearing state are similar to the other disease states that feature involuntary weight loss and skeletal muscle atrophy. These states are generally characterized by altered BCAA availability (low BCAA intakes, elevated rates of BCAA oxidation, and gluconeogenesis), which are concurrent with activation of proteolysis and suppression of protein synthesis in skeletal muscle and ultimately lead to erosion of lean tissue mass. These features in turn imply BCAA deficiency compared with whole-body requirements and are the basis of suggestions for dietary supplementation with BCAA or their metabolites. Recent studies on BCAA supplementation in cancer focus on leucine and its derivative, beta-methyl beta-hydroxybutyrate, as regulators of skeletal muscle metabolism, although their relative efficacy is unknown. However, what would otherwise be a relatively straightforward consideration of amino acid supply and demand is confounded by the presence of the tumor and its potential utilization of BCAA for its proliferative and invasive activities. Positron emission tomography with (11)C-leucine, used for in vivo tumor imaging, points to the high avidity of tumor amino acid uptake. These features have incited research in opposing directions, probing BCAA deprivation, with a view to limiting tumor growth, as well as BCAA supplementation, with a view to supporting maintenance of host lean tissue. No clear conclusion is presently available from the sum of these efforts. Animal models with relevant clinical features are essential to determine if amino acid therapy can alter the balance between the host and the tumor in a manner that favors the host overall.
Collapse
Affiliation(s)
- Vickie E Baracos
- Department of Agricultural, Food, and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada.
| | | |
Collapse
|
|
9
|
He YC, Wang YH, Cao J, Chen JW, Pan DY, Zhou YK. Effect of complex amino acid imbalance on growth of tumor in tumor-bearing rats. World J Gastroenterol 2003; 9:2772-5. [PMID: 14669331 PMCID: PMC4612050 DOI: 10.3748/wjg.v9.i12.2772] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the effect of complex amino acid imbalance on the growth of tumor in tumor-bearing (TB) rats.
METHODS: Sprague-Dawlley (SD) rats underwent jejunostomy for nutritional support. A suspension of Walker-256 carcinosarcoma cells was subcutaneously inoculated. TB rats were randomly divided into groups A, B, C and D according to the formula of amino acids in enteral nutritional solutions, respectively. TB rats received jejunal feedings supplemented with balanced amino acids (group A), methionine-depleted amino acids (group B), valine-depleted amino acids (group C) and methionine- and valine-depleted complex amino acid imbalance (group D) for 10 days. Tumor volume, inhibitory rates of tumor, cell cycle and life span of TB rats were investigated.
RESULTS: The G0/G1 ratio of tumor cells in group D (80.5 ± 9.0)% was higher than that in groups A, B and C which was 67.0% ± 5.1%, 78.9% ± 8.5%, 69.2% ± 6.2%, respectively (P < 0.05). The ratio of S/G2M and PI in group D were lower than those in groups A, B and C. The inhibitory rate of tumor in groups B, C and D was 37.2%, 33.3% and 43.9%, respectively (P < 0.05). The life span of TB rats in group D was significantly longer than that in groups B, C, and A.
CONCLUSION: Methionine/valine-depleted amino acid imbalance can inhibit tumor growth. Complex amino acids of methionine and valine depleted imbalance have stronger inhibitory effects on tumor growth.
Collapse
Affiliation(s)
- Yin-Cheng He
- Department of General Surgery, Zhongnan Hospital, Wuhan University, Wuhan 430071, Hubei Province, China.
| | | | | | | | | | | |
Collapse
|
|
10
|
He YC, Cao J, Chen JW, Pan DY, Zhou YK. Influence of methionine/valine-depleted enteral nutrition on nucleic acid and protein metabolism in tumor-bearing rats. World J Gastroenterol 2003; 9:771-4. [PMID: 12679929 PMCID: PMC4611447 DOI: 10.3748/wjg.v9.i4.771] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
AIM: To investigate the effects of methionine/valine-depleted enteral nutrition (EN) on RNA, DNA and protein metabolism in tumor-bearing (TB) rats.
METHODS: Sprague-Dawlley (SD) rats underwent jejunostomy for nutritional support. A suspension of Walker-256 carcinosarcoma cells was subcutaneously inoculated. 48 TB rats were randomly divided in 4 groups: A, B, C and D. The TB rats had respectively received jejunal feedings supplemented with balanced amino acids, methionine-depleted, balanced amino acids and valine-depleted for 6 d before injection of 740 KBq 3H- methionine/valine via jejunum. The 3H incorporation rate of the radioactivity into RNA, DNA and proteins in tumor tissues at 0.5, 1, 2, 4 h postinjection of tracers was assessed with liquid scintillation counter.
RESULTS: Incorporation of 3H into proteins in groups B and D was (0.500 ± 0.020)% to (3.670 ± 0.110)% and (0.708 ± 0.019)% to (3.813 ± 0.076)% respectively, lower than in groups A [(0.659 ± 0.055)% to (4.492 ± 0.108)%] and C [(0.805 ± 0.098)% to (4.180 ± 0.018)%]. Incorporation of 3H into RNA, DNA in group B was (0.237 ± 0.075)% and (0.231 ± 0.052)% respectively, lower than in group A (P < 0.01). There was no significant difference in uptake of 3H by RNA and DNA between group C and D (P > 0.05).
CONCLUSION: Protein synthesis was inhibited by methionine/valine starvation in TB rats and nucleic acid synthesis was reduced after methionine depletion, thus resulting in suppression of tumor growth.
Collapse
Affiliation(s)
- Yin-Cheng He
- Department of general surgery, Zhongnan Hospital, Wuhan University, Wuhan 430071, China.
| | | | | | | | | |
Collapse
|
|
11
|
Affiliation(s)
- J M Argilés
- Department de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, Spain.
| | | | | |
Collapse
|
|
12
|
Komatsu H, Nishihira T, Chin M, Doi H, Shineha R, Mori S, Satomi S. Effects of caloric intake on anticancer therapy in rats with valine-depleted amino acid imbalance. Nutr Cancer 1997; 28:107-12. [PMID: 9200158 DOI: 10.1080/01635589709514560] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Valine-depleted amino acid imbalance solution markedly inhibits tumor growth but causes fatty liver as a side effect. However, much remains unknown about the mechanism of the development of fatty liver. Valine-depleted amino acid imbalance solution containing various concentrations of calories was administered to tumor-bearing rats for four days by means of total parenteral nutritional methods to investigate the interaction of caloric intake and the development of fatty liver. Compared with the total parenteral nutrition control group the triglyceride content of the liver rose significantly in the group given valine-depleted amino acid imbalance solution with an increase in caloric intake. Plasma total protein and albumin significantly decreased. The very-low-density lipoprotein concentration in serum was also significantly lower than that in the control group. Valine-depleted amino acid imbalance caused hypoproteinemia, suggesting a fall in synthesis of apolipoproteins in the liver indispensable for lipid release. Along with the increase in the total caloric intake, triglyceride synthesis in the liver increased, resulting in augmentation of fatty content of the liver, probably because of the decreased lipid release.
Collapse
Affiliation(s)
- H Komatsu
- Second Department of Surgery, Tohoku University School of Medicine, Sendai, Japan
| | | | | | | | | | | | | |
Collapse
|
|
13
|
Nishihira T, Komatsu H, Sagawa J, Shineha R, Mori S. Prevention of fatty liver and maintenance of systemic valine depletion using a newly developed dual infusion system. JPEN J Parenter Enteral Nutr 1995; 19:199-203. [PMID: 8551647 DOI: 10.1177/0148607195019003199] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
BACKGROUND Valine-depleted amino acid imbalance, while having a suppressive effect on tumor growth, may induce fatty liver. METHODS We administered a valine-depleted total parenteral nutrition (TPN) solution by the central venous route to non-tumor-bearing rats and examined the time course of the development of fatty liver. In an attempt to prevent this condition, we administered a continuous infusion of low concentrations of valine via the portal vein simultaneously with administration of central venous valine-depleted nutrition for 4 days. RESULTS A marked accumulation of triglyceride was observed in the liver on day 4 of the administration of valine-depleted nutrition. It is speculated that such accumulation is the cause of fatty liver. The level of valine in the peripheral blood began to decrease soon after administration was begun and resulted in a state of systemic valine deficiency. Rats given 25% or more of the valine concentration in the standard TPN solution via the portal vein simultaneously with the administration of central venous valine-depleted nutrition, had a triglyceride level similar to that of the control group. The group given 50% or less of the valine concentration had a level of valine in the peripheral blood as low as that of the valine-depleted group, indicating the maintenance of a valine-deficient state. CONCLUSION Administration of low concentrations of valine via the portal vein simultaneous with central venous administration of valine-depleted TPN solution may prevent fatty liver.
Collapse
Affiliation(s)
- T Nishihira
- Second Department of Surgery, Tohoku University School of Medicine, Sendai, Japan
| | | | | | | | | |
Collapse
|