基于脂质代谢异常探讨“痰浊”理论在肝细胞癌微环境中的生物学内涵

杨芳明; 肖准; 陈晓琦; 张传雷; 陈欣菊; 马素平; 赵文霞

doi:10.3969/j.issn.1001-5256.2023.02.029

基于脂质代谢异常探讨“痰浊”理论在肝细胞癌微环境中的生物学内涵

DOI: 10.3969/j.issn.1001-5256.2023.02.029

杨芳明¹,
肖准¹,
陈晓琦¹,
张传雷¹,
陈欣菊¹,
马素平¹,
赵文霞^{1, 2, , ,}

1.
河南中医药大学第一附属医院脾胃肝胆病科，郑州 450000
2.
河南中医药大学，郑州 450000

基金项目:

国家科技重大专项课题 (SQ2018ZX100303);

国家自然科学基金 (82205021);

河南省特色骨干学科中医学第二批学科建设项目 (STG-ZYX01-202101);

河南省中医药科学研究专项课题 (2022JDZX018);

河南中医药大学第一附属医院博士科研启动基金 (2021BSJJ007)

利益冲突声明：所有作者均声明不存在利益冲突。

作者贡献声明：杨芳明负责论文思路设计与撰写；肖准修改论文与做图；陈晓琦、张传雷、陈欣菊、马素平负责思路修改；赵文霞指导文章撰写并最后定稿。

详细信息

通信作者:
赵文霞，zhao-wenxia@163.com (ORCID: 0000-0001-6666-9469)

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出版历程
- 收稿日期: 2022-06-21
- 录用日期: 2022-08-18
- 出版日期: 2023-02-20

Biological connotation of "phlegm-turbidity" theory in hepatocellular carcinoma microenvironment based on abnormal lipid metabolism

1.
Department of Hepatology and Spleen-Stomach, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou 450000, China
2.
Henan University of Chinese Medicine, Zhengzhou 450000, China

Research funding:

National Science and Technology Major Project (SQ2018ZX100303);

National Natural Science Foundation of China (82205021);

The Second Batch of Discipline Construction Projects of Traditional Chinese Medicine in Henan Province's Characteristic Backbone Discipline (STG-ZYX01-202101);

Henan Province Traditional Chinese Medicine Scientific Research Special Project (2022JDZX018);

The Doctoral Research Foundation of the First Affiliated Hospital of Henan University of Traditional Chinese Medicine (2021BSJJ007)

More Information

Corresponding author: ZHAO Wenxia, zhao-wenxia@163.com (ORCID: 0000-0001-6666-9469)

摘要

摘要: 肝癌的防治目前仍缺乏有效策略，对其发病机制的深入认识有助于开发新的治疗手段。由于脂质代谢在肝癌发生发展中的异常改变，其变化过程与中医“痰浊”理论密切相关。本文将从肝细胞癌微环境中脂质代谢变化入手，探讨脂质代谢在肿瘤细胞和免疫细胞群的异常改变与“痰浊”理论的相关性，以及临床应用化痰相关治法所取得的疗效。由于中医“痰浊”理论的致病特性在肝癌发病和病机变化中具有重要作用，因此对其理论内涵的分析有助于病理机制的阐明，也为中医药发挥防治肝癌作用提供理论依据。
- 癌, 肝细胞 /
- 脂类代谢 /
- 痰浊 /
- 医学, 中国传统
Abstract: There is still a lack of effective strategies for the prevention and treatment of liver cancer, and a deep understanding of its pathogenesis may help to develop new treatment methods. Due to the abnormal changes of lipid metabolism in the development and progression of liver cancer, such process is closely associated with the "phlegm-turbidity" theory in traditional Chinese medicine (TCM). Starting from the changes of lipid metabolism in hepatocellular carcinoma microenvironment, this article discusses the association of the abnormal changes of lipid metabolism in tumor cells and immune cells with the "phlegm-turbidity" theory and the clinical efficacy of phlegm-eliminating therapies in clinical practice. Since the "phlegm-turbidity" theory in TCM plays an important role in the pathogenesis and pathological changes of liver cancer, the analysis of its theoretical connotation helps to clarify pathological mechanism, thereby providing a theoretical basis for the role of TCM in the prevention and treatment of liver cancer.
- Carcinoma, Hepatocellular /
- Lipid Metabolism /
- Phlegm Turbidity /
- Medicine, Chinese Traditional

HTML全文

图 1 HCC肿瘤细胞脂质代谢改变

注：a，NAFLD相关HCC肿瘤细胞脂质代谢；b，β-catenin激活的HCC肿瘤细胞脂质代谢。红色：增加；蓝色：减少。SCD，硬脂酰辅酶A去饱和酶；MUFA，单不饱和脂肪酸；ACS，酰基辅酶A合成酶；FASN，脂肪酸合酶；CACT，肉毒碱脂酰转移酶；TCA，三羧酸循环；ATP，腺嘌呤核苷三磷酸；ACL，ATP-柠檬酸裂解酶；ACC，乙酰辅酶A羧化酶；CoA，辅酶A；Acyl-CoA，酰基辅酶A；Acetyl-CoA，乙酰辅酶A；Malonyl-CoA，丙二酰辅酶A。

Figure 1. Changes of lipid metabolism in HCC tumor cells

下载: 全尺寸图片幻灯片

图 2 HCC肿瘤细胞及免疫细胞脂质代谢变化

Figure 2. Changes of lipid metabolism in HCC tumor cells and immune cells

下载: 全尺寸图片幻灯片

参考文献(44)

[1]	TAHMASEBI BIRGANI M, CARLONI V. Tumor microenvironment, a paradigm in hepatocellular carcinoma progression and therapy[J]. Int J Mol Sci, 2017, 18(2): 405. DOI: 10.3390/ijms18020405.
[2]	ZHUANG TZ, CHEN YB, AN HY. Discussion on TCM differentiation of primary liver cancer[J]. Forum Tradit Chin Med, 2021, 36(1): 18-19. DOI: 10.13913/j.cnki.41-1110/r.2021.01.008. 庄桐粧, 陈钰冰, 安海燕. 原发性肝癌中医辨证探讨[J]. 国医论坛, 2021, 36(1): 18-19. DOI: 10.13913/j.cnki.41-1110/r.2021.01.008.
[3]	BAO MH, WONG CC. Hypoxia, metabolic reprogramming, and drug resistance in liver cancer[J]. Cells, 2021, 10(7): 1715. DOI: 10.3390/cells10071715.
[4]	ZHAO WX, CHEN XJ. Principles and regimens for traditional Chinese medicine diagnosis and treatment of primary liver cancer[J]. J Clin Hepatol, 2021, 37(9): 2005-2008. DOI: 10.3969/j.issn.1001-5256.2021.09.002. 赵文霞, 陈欣菊. 原发性肝癌中医药诊疗原则及方案构建[J]. 临床肝胆病杂志, 2021, 37(9): 2005-2008. DOI: 10.3969/j.issn.1001-5256.2021.09.002.
[5]	GU KB, ZHANG LN, WU J, et al. Research progress on resolving phlegm method on the treatment of malignant tumors[J]. China J Tradit Chin Med Pharma, 2017, 32(12): 5468-5471. https://www.cnki.com.cn/Article/CJFDTOTAL-BXYY201712062.htm 顾恪波, 张丽娜, 吴洁, 等. "化痰"法治疗恶性肿瘤的研究进展[J]. 中华中医药杂志, 2017, 32(12): 5468-5471. https://www.cnki.com.cn/Article/CJFDTOTAL-BXYY201712062.htm
[6]	LU C, RONG D, ZHANG B, et al. Current perspectives on the immunosuppressive tumor microenvironment in hepatocellular carcinoma: challenges and opportunities[J]. Mol Cancer, 2019, 18(1): 130. DOI: 10.1186/s12943-019-1047-6.
[7]	ZHANG JS. A preliminary study on the treatment of hyperlipidemia from the liver[J]. J New Chin Med, 2006, 38(11): 6-9. DOI: 10.3969/j.issn.0256-7415.2006.11.003. 张金生. 高脂血症从肝论治初探[J]. 新中医, 2006, 38(11): 6-9. DOI: 10.3969/j.issn.0256-7415.2006.11.003.
[8]	XUE X, LI HY, LI YM, et al. Study on the mechanism of treating fatty liver from phleg[J]. Chin J Basic Med Tradit Chin Med, 2014, 20(11): 1472-1475. https://www.cnki.com.cn/Article/CJFDTOTAL-ZYJC201411009.htm 薛欣, 李海玉, 李玉梅, 等. 从痰论治脂肪肝机制探讨[J]. 中国中医基础医学杂志, 2014, 20(11): 1472-1475. https://www.cnki.com.cn/Article/CJFDTOTAL-ZYJC201411009.htm
[9]	HALL Z, CHIARUGI D, CHARIDEMOU E, et al. Lipid remodeling in hepatocyte proliferation and hepatocellular carcinoma[J]. Hepatology, 2021, 73(3): 1028-1044. DOI: 10.1002/hep.31391.
[10]	HU B, LIN JZ, YANG XB, et al. Aberrant lipid metabolism in hepatocellular carcinoma cells as well as immune microenvironment: A review[J]. Cell Prolif, 2020, 53(3): e12772. DOI: 10.1111/cpr.12772.
[11]	FUJIWARA N, NAKAGAWA H, ENOOKU K, et al. CPT2 downregulation adapts HCC to lipid-rich environment and promotes carcinogenesis via acylcarnitine accumulation in obesity[J]. Gut, 2018, 67(8): 1493-1504. DOI: 10.1136/gutjnl-2017-315193.
[12]	LU GD, ANG YH, ZHOU J, et al. CCAAT/enhancer binding protein α predicts poorer prognosis and prevents energy starvation-induced cell death in hepatocellular carcinoma[J]. Hepatology, 2015, 61(3): 965-978. DOI: 10.1002/hep.27593.
[13]	SENNI N, SAVALL M, CABRERIZO GRANADOS D, et al. β-catenin-activated hepatocellular carcinomas are addicted to fatty acids[J]. Gut, 2019, 68(2): 322-334. DOI: 10.1136/gutjnl-2017-315448.
[14]	NAKAGAWA H, HAYATA Y, KAWAMURA S, et al. Lipid metabolic reprogramming in hepatocellular carcinoma[J]. Cancers (Basel), 2018, 10(11): 447. DOI: 10.3390/cancers10110447.
[15]	ZENG ZR, CHEN MH, WANG GW. WangGuowei's Clinical Experience in Treating Hepatitis from Perspective of Heat-Damp Theory[J]. J Chengdu Univ Tradit Chin Med, 2021, 44(2): 66-69. DOI: 10.13593/j.cnki.51-1501/r.2021.02.066. 曾振锐, 陈敏华, 王国玮. 王国玮从湿热论治肝炎临床经验撷要[J]. 成都中医药大学学报, 2021, 44(2): 66-69. DOI: 10.13593/j.cnki.51-1501/r.2021.02.066.
[16]	CHO HK, KIM SY, YOO SK, et al. Fatty acids increase hepatitis B virus X protein stabilization and HBx-induced inflammatory gene expression[J]. FEBS J, 2014, 281(9): 2228-2239. DOI: 10.1111/febs.12776.
[17]	KIM KH, HONG SP, KIM K, et al. HCV core protein induces hepatic lipid accumulation by activating SREBP1 and PPARgamma[J]. Biochem Biophys Res Commun, 2007, 355(4): 883-888. DOI: 10.1016/j.bbrc.2007.02.044.
[18]	IOANNOU GN. Epidemiology and risk-stratification of NAFLD-associated HCC[J]. J Hepatol, 2021, 75(6): 1476-1484. DOI: 10.1016/j.jhep.2021.08.012.
[19]	GUO J, YE LL, GUO YQ, et al. Discussion on the differentiation and treatment of nonalcoholic fatty liver from the perspective of 'turbidity and coagulation'[J]. China J Tradit Chin Med Pharma, 2020, 35(4): 1885-1887. https://www.cnki.com.cn/Article/CJFDTOTAL-BXYY202004072.htm 郭静, 叶琳琳, 郭玉琴, 等. 从"浊阴凝痞"视角探讨非酒精性脂肪肝病辨治思路[J]. 中华中医药杂志, 2020, 35(4): 1885-1887. https://www.cnki.com.cn/Article/CJFDTOTAL-BXYY202004072.htm
[20]	SANGINETO M, VILLANI R, CAVALLONE F, et al. Lipid metabolism in development and progression of hepatocellular carcinoma[J]. Cancers (Basel), 2020, 12(6): 1419. DOI: 10.3390/cancers12061419.
[21]	LI Z, GUAN M, LIN Y, et al. Aberrant lipid metabolism in hepatocellular carcinoma revealed by liver lipidomics[J]. Int J Mol Sci, 2017, 18(12): 2550. DOI: 10.3390/ijms18122550.
[22]	BERNDT N, ECKSTEIN J, HEUCKE N, et al. Characterization of lipid and lipid droplet metabolism in human HCC[J]. Cells, 2019, 8(5): 512. DOI: 10.3390/cells8050512.
[23]	PAVLOVA NN, THOMPSON CB. The emerging hallmarks of cancer metabolism[J]. Cell Metab, 2016, 23(1): 27-47. DOI: 10.1016/j.cmet.2015.12.006.
[24]	YANG YF, LIU JT. Study on biomarkers of phlegm dampness syndrome in metabolic syndrome based on metabonomics[J]. Lishizhen Med Mater Med Res, 2020, 31(2): 509-512. https://www.cnki.com.cn/Article/CJFDTOTAL-SZGY202002085.htm 杨宇峰, 刘军彤. 基于代谢组学的代谢综合征痰湿证生物标志物研究[J]. 时珍国医国药, 2020, 31(2): 509-512. https://www.cnki.com.cn/Article/CJFDTOTAL-SZGY202002085.htm
[25]	WANG Q, DONG J, WU HD, et al. Molecular biological characteristics of phlegm dampness constitution[J]. Strat Study Chin Acad Engin, 2008, 10(7): 100-103. https://www.cnki.com.cn/Article/CJFDTOTAL-GCKX200807018.htm 王琦, 董静, 吴宏东, 等. 痰湿体质的分子生物学特征[J]. 中国工程科学, 2008, 10(7): 100-103. https://www.cnki.com.cn/Article/CJFDTOTAL-GCKX200807018.htm
[26]	LI Z, WU T, ZHENG B, et al. Individualized precision treatment: Targeting TAM in HCC[J]. Cancer Lett, 2019, 458: 86-91. DOI: 10.1016/j.canlet.2019.05.019.
[27]	SU P, WANG Q, BI E, et al. Enhanced lipid accumulation and metabolism are required for the differentiation and activation of tumor-associated macrophages[J]. Cancer Res, 2020, 80(7): 1438-1450. DOI: 10.1158/0008-5472.CAN-19-2994.
[28]	ZHANG Q, LOU Y, BAI XL, et al. Immunometabolism: A novel perspective of liver cancer microenvironment and its influence on tumor progression[J]. World J Gastroenterol, 2018, 24(31): 3500-3512. DOI: 10.3748/wjg.v24.i31.3500.
[29]	PACELLA I, PROCACCINI C, FOCACCETTI C, et al. Fatty acid metabolism complements glycolysis in the selective regulatory T cell expansion during tumor growth[J]. Proc Natl Acad Sci U S A, 2018, 115(28): E6546-E6555. DOI: 10.1073/pnas.1720113115.
[30]	TRAN JANCO JM, LAMICHHANE P, KARYAMPUDI L, et al. Tumor-infiltrating dendritic cells in cancer pathogenesis[J]. J Immunol, 2015, 194(7): 2985-2991. DOI: 10.4049/jimmunol.1403134.
[31]	EVERTS B, AMIEL E, HUANG SC, et al. TLR-driven early glycolytic reprogramming via the kinases TBK1-IKKε supports the anabolic demands of dendritic cell activation[J]. Nat Immunol, 2014, 15(4): 323-332. DOI: 10.1038/ni.2833.
[32]	WCULEK SK, KHOUILI SC, PRIEGO E, et al. Metabolic control of dendritic cell functions: digesting information[J]. Front Immunol, 2019, 10: 775. DOI: 10.3389/fimmu.2019.00775.
[33]	ZHANG SQ, HU H, LUO SJ, et al. Immune mechanism of the internal environment of spleen deficiency in liver cancer[J]. Lishizhen Med Mater Med Res, 2020, 31(8): 1961-1963. DOI: 10.3969/j.issn.1008-0805.2020.08.059 张书侨, 胡浩, 罗绍驹, 等. 肝癌脾虚内环境境免疫机制研究[J]. 时珍国医国药, 2020, 31(8): 1961-1963. DOI: 10.3969/j.issn.1008-0805.2020.08.059
[34]	ZHAO CL. "Liver controlling conveyance and dispersion" act as the core of regulating immunologic function[J]. J Tradit Chin Med, 2017, 58(7): 568-571. DOI: 10.13288/j.11-2166/r.2017.07.009. 赵昌林. 肝主疏泄为调控免疫功能的核心[J]. 中医杂志, 2017, 58(7): 568-571. DOI: 10.13288/j.11-2166/r.2017.07.009.
[35]	SUN MQ, HU KW, ZHOU T. Discussion on the related mechanism of tumor metastasis and tumor microenvironment based on phlegm[J]. Western J Traditl Chin Med, 2019, 32(10): 15-18. https://www.cnki.com.cn/Article/CJFDTOTAL-GSZY201910005.htm 孙满强, 胡凯文, 周天. 从痰论治肿瘤微环境与肿瘤转移相关作用机制[J]. 西部中医药, 2019, 32(10): 15-18. https://www.cnki.com.cn/Article/CJFDTOTAL-GSZY201910005.htm
[36]	YUAN JH, WU Y. Related theories of spleen-invigorating and phlegm-removing therapy and its application in treatment of liver cancer[J]. J Liaoning Univ Tradit Chin Med, 2012, 14(6): 85-87. DOI: 10.13194/j.jlunivtcm.2012.06.87.yuanjh.118. 袁菊花, 吴煜. 健脾化痰法在肝癌治疗中的相关理论及应用[J]. 辽宁中医药大学学报, 2012, 14(6): 85-87. DOI: 10.13194/j.jlunivtcm.2012.06.87.yuanjh.118.
[37]	SUN C, WU Y, CHEN YL, et al. Clinical effect of the phlegm-eliminating, phlegm-dissolving, and phlegm-removing methods in treatment of primary liver cancer: An analysis of 3 proven cases[J]. Jiangsu J Traditi Chin Med, 2013, 45(3): 67-68. DOI: 10.3969/j.issn.1672-397X.2013.03.044. 孙超, 吴煜, 陈永伦, 等. 治痰三法治疗原发性肝癌的探讨——附验案3则[J]. 江苏中医药, 2013, 45(3): 67-68. DOI: 10.3969/j.issn.1672-397X.2013.03.044.
[38]	LI B, WANG YH, ZHANG XF. Clinical effect of spleen-invigorating, phlegm-dissolving, and static blood-resolving prescription in treatment of advanced primary liver cancer[J]. Liaoning J Tradit Chin Med, 2014, 41(1): 108-110. DOI: 10.13192/j.issn.1000-1719.2014.01.047. 李斌, 王玉华, 张霄峰. 健脾消痰散结方治疗中晚期原发性肝癌临床观察[J]. 辽宁中医杂志, 2014, 41(1): 108-110. DOI: 10.13192/j.issn.1000-1719.2014.01.047.
[39]	LIANG Q, LUO PJ, ZENG SM, et al. Huang Gui-hua's Experience of Treating Primary Liver Cancer[J]. Henan Tradit Chin Med, 2020, 40(8): 1204-1207. DOI: 10.16367/j.issn.1003-5028.2020.08.0305. 梁琪, 罗鹏基, 曾思敏, 等. 薛博瑜治疗原发性肝癌经验[J]. 河南中医, 2020, 40(8): 1204-1207. DOI: 10.16367/j.issn.1003-5028.2020.08.0305.
[40]	YUE Y. Experience in the four methods of Professor Xue Boyu in syndrome differentiation-based treatment of liver cancer[J]. Global Tradit Chin Med, 2016, 9(1): 56-57. DOI: 10.16367/j.issn.1003-5028.2020.08.0305. 岳煜. 薛博瑜教授辨治肝癌四法经验探析[J]. 环球中医药, 2016, 9(1): 56-57. DOI: 10.16367/j.issn.1003-5028.2020.08.0305.
[41]	QIU XY, JIA LQ, SONG N, et al. Study on effect and mechanism of huayu qutan fomula on mice with high-fat and liver cancer based on ferroptosis related protein[J]. Chin Arch Tradit Chin Med, 2021, 39(9): 137-141, 273. DOI: 10.13193/j.issn.1673-7717.2021.09.035 裘雪莹, 贾连群, 宋囡, 等. 基于铁死亡相关蛋白探讨化瘀祛痰方对高脂合并肝癌小鼠的影响及机制[J]. 中华中医药学刊, 2021, 39(9): 137-141, 273. DOI: 10.13193/j.issn.1673-7717.2021.09.035.
[42]	ZHANG CA, GU YF, ZHANG YC, et al. Clinical thinking of treating recurrence and metastasis of liver cancer from phlegm[J]. J Oncol Chin Med, 2020, 2(1): 31-35. DOI: 10.19811/j.cnki.ISSN2096-6628.2020.01.008. 张慈安, 顾雨芳, 张映城, 等. 浅析从痰论治肝癌复发转移的临床思路[J]. 中医肿瘤学杂志, 2020, 2(1): 31-35. DOI: 10.19811/j.cnki.ISSN2096-6628.2020.01.008.
[43]	LI X, YU H, GONG Y, et al. Fuzheng Xiaozheng prescription relieves rat hepatocellular carcinoma through improving anti-inflammation capacity and regulating lipid related metabolisms[J]. J Ethnopharmacol, 2022, 284: 114801. DOI: 10.1016/j.jep.2021.114801.
[44]	YANG L, ZHANG X, LUO CY, et al. Research progress on mechanism of TCM based on lipid metabolism in prevention and treatment of liver cancer[J]. Global Tradit Chin Med, 2022, 15(6): 1100-1104. DOI: 10.3969/j.issn.1674-1749.2022.06.038. 杨岚, 张鑫, 罗春玉, 等. 基于脂质代谢的中医药防治肝癌作用机制研究进展[J]. 环球中医药, 2022, 15(6): 1100-1104. DOI: 10.3969/j.issn.1674-1749.2022.06.038.