乙型肝炎病毒感染者血清脂蛋白亚类及其组分的定量特征

doi:10.3969/j.issn.1674-8115.2023.02.002

上海交通大学学报（医学版） ›› 2023, Vol. 43 ›› Issue (2): 143-151.doi: 10.3969/j.issn.1674-8115.2023.02.002

• 论著 · 基础研究 • 上一篇

乙型肝炎病毒感染者血清脂蛋白亚类及其组分的定量特征

易小璇¹(), 胡森林², 孙阳², 黄庆霞¹(), 唐惠儒¹^,³()

^1.复旦大学生命科学学院，人类表型组研究院，遗传工程国家重点实验室，代谢组学与系统生物学实验室，上海 200438
^2.华中科技大学同济医学院附属同济医院心血管内科，武汉 430030
^3.复旦大学附属中山医院，上海 200032

收稿日期:2022-12-08 接受日期:2023-02-03 出版日期:2023-02-28 发布日期:2023-02-28
通讯作者: 黄庆霞,唐惠儒 E-mail:yixiaoxuanyxx@126.com;qingxhuang@fudan.edu.cn;huiru_tang@fudan.edu.cn
作者简介:易小璇（1993—），女，硕士生；电子信箱：yixiaoxuanyxx@126.com。
基金资助:
国家重点研发计划(2021YFC2500600);国家自然科学基金(31821002)

Quantitative characteristics of serum lipoprotein phenotypes for HBV patients

YI Xiaoxuan¹(), HU Senlin², SUN Yang², HUANG Qingxia¹(), TANG Huiru¹^,³()

^1.School of Life Sciences, Human Phenome Institute, State Key Laboratory of Genetic Engineering, Metabonomics and Systems Biology Laboratory at Shanghai International Centre for Molecular Phenomics, Shanghai 200438, China
^2.Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
^3.Zhongshan Hospital, Fudan University, Shanghai 200032, China

Received:2022-12-08 Accepted:2023-02-03 Online:2023-02-28 Published:2023-02-28
Contact: HUANG Qingxia,TANG Huiru E-mail:yixiaoxuanyxx@126.com;qingxhuang@fudan.edu.cn;huiru_tang@fudan.edu.cn
Supported by:
National Key R&D Program of China(2021YFC2500600);National Natural Science Foundation of China(31821002)

摘要/Abstract

摘要：

目的·既往研究发现乙型肝炎病毒（hepatitis B virus，HBV）感染会引起宿主脂蛋白改变，但脂蛋白亚类及其组分对HBV感染的应答规律未见报道。该研究拟通过定量分析HBV感染者的血清脂蛋白亚类及其组分，研究HBV感染引起的血清脂蛋白谱的变化特征。方法·纳入2017年3—6月就诊于华中科技大学同济医学院附属同济医院心内科的乙型肝炎病毒表面抗原阳性［HBsAg（+）］患者（n=40），同期纳入40例HBsAg阴性［HBsAg（-）］对照人群。使用核磁共振氢谱（proton nuclear magnetic resonance，¹H-NMR）定量分析血清脂蛋白亚类及其组分，通过正交偏最小二乘判别分析、组间差异分析、逻辑回归分析和Spearman相关分析探索慢性HBV患者血清脂蛋白谱的变化规律。结果·HBsAg（+）组中大部分脂蛋白亚类及其组分水平显著低于HBsAg（-）组。校正年龄、性别、高血压、糖尿病以及心血管疾病因素后，总极低密度脂蛋白（very-low density lipoprotein，VLDL）、VLDL1~VLDL3、中间密度脂蛋白（intermediate-density lipoprotein，IDL）、小颗粒的高密度脂蛋白（small high-density lipoprotein 4，HDL4）和non-HDL及其组分依然是HBV感染的保护因素（OR<1，P<0.01），而VLDL5中的三酰甘油（triacylglycerol，TAG）占总脂质（total lipid，LP）的百分比［VLDL5-（TAG/LP）］则是HBV感染的危险因素（OR>1，P<0.01）。此外，HBsAg（+）人群的炎症程度与HDL4中的脂质组分水平高度负相关（r在-0.71~-0.51之间，P≤0.002）。通过特征筛选获得6个脂蛋白亚类指标，构建HBV感染诊断模型的AUC为0.861。结论·HBV感染影响肝脏分泌的脂蛋白的代谢转化，且脂蛋白亚类及其组分可用以区分HBV引起的表面抗原阳性患者。

关键词: 脂蛋白, ¹H-NMR, 乙型肝炎病毒, 慢性乙型肝炎

Abstract:

Objective ·Previous studies showed that hepatitis B virus (HBV) infection caused outstanding changes in host lipoproteins. However, there are no reports on such component changes of lipoprotein subfractions. This study aimed to quantify the HBV-caused changes in the serum lipoprotein subfractions and their components. Methods ·Hepatitis B surface antigen-positive [HBsAg (+)] patients at Division of Cardiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology from March to June 2017 were included (n=40), and 40 HBsAg-negative [HBsAg (-)] population were matched as controls. Serum lipoprotein subfractions and their components were quantified by using ¹H-NMR. Orthogonal partial least-squares discriminant analysis (OPLS-DA), variance analysis between the two groups, logistic regression analysis and Spearman correlation analysis were conducted to reveal the lipoprotein changes in chronic HBV patients against controls. Results ·HBsAg (+) population had significantly lower levels in most lipoprotein subfractions than HBsAg (-) population. After adjustments for age, gender, hypertension, diabetes mellitus and coronary heart disease, the levels of total VLDL, VLDL1-VLDL3, IDL, HDL4, non-HDL and their components were protective factors for HBV infection (OR < 1, P < 0.01). In contrast, VLDL5-(TAG/LP) was a risk factor for HBV infection (OR > 1, P < 0.01). In addition, the severity of inflammation in the HBsAg (+) population was negatively correlated with the levels of lipids in HDL4 with correlation coefficient ranging from -0.71 to -0.51(P≤ 0.002). Six lipoprotein subfractions were obtained through feature screening, and the AUC of HBV infection diagnosis model was 0.861. Conclusion ·HBV infection causes significant changes in liver-excretion of lipoproteins and their circulation metabolism; the lipoprotein phenotypes can differentiate HBV-infected patients from controls.

Key words: lipoprotein, ¹H-NMR, hepatitis B virus, chronic hepatitis B

中图分类号:

R33.1

易小璇, 胡森林, 孙阳, 黄庆霞, 唐惠儒. 乙型肝炎病毒感染者血清脂蛋白亚类及其组分的定量特征[J]. 上海交通大学学报（医学版）, 2023, 43(2): 143-151.

YI Xiaoxuan, HU Senlin, SUN Yang, HUANG Qingxia, TANG Huiru. Quantitative characteristics of serum lipoprotein phenotypes for HBV patients[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2023, 43(2): 143-151.

图/表 4

表1 HBsAg （-）和HBsAg （+）人群的基线特征

Tab 1 Baseline characteristics of HBsAg （-） and HBsAg （+） populations

Characteristic	HBsAg （-）（n = 40）	HBsAg （+）（n = 35）	P value
Age/year	57.75 ± 9.15	58.66 ± 9.08	0.669
Gender （male）/n（%）	24 （60.00）	22 （62.86）	0.800
Hyperlipidemia/n（%）	2 （5.00）	3 （8.57）	0.877
Hypertension/n （%）	18 （45.00）	18 （51.43）	0.578
Diabetes/n（%）	11 （27.50）	13 （37.14）	0.372
CHD/n（%）	25 （62.50）	26 （74.29）	0.275
GPT/（U·L^-1）	22.20 ± 13.19	31.97 ± 34.24	0.310
GOT/（U·L^-1）	24.75 ± 19.94	33.31 ± 26.31	0.030
hsCRP/（mg·L^-1）	8.52 ± 28.90	1.25 ± 2.92	0.735
HCY/（μmol·L^-1）	11.74 ± 6.27	13.24 ± 6.62	0.319
Creatinine/（μmol·L^-1）	75.23 ± 14.80	72.83 ± 16.86	0.514
UA/（μmol·L^-1）	329.69 ± 95.37	314.88 ± 97.70	0.509
Glucose/（mmol·L^-1）	6.71 ± 4.47	6.76 ± 3.63	0.729
CH/（mmol·L^-1）	4.14 ± 0.77	3.68 ± 0.90	0.017
TAG/（mmol·L^-1）	1.70 ± 1.10	1.44 ± 0.76	0.339
HDL-Ch/（mmol·L^-1）	1.14 ± 0.22	1.09 ± 0.32	0.412
LDL-Ch/（mmol·L^-1）	2.41 ± 0.75	2.07 ± 0.57	0.032

图1 HBsAg(+)和HBsAg(-)人群的血清脂蛋白的变化特征Note： A. OPLS-DA score plot. B. 42 significantly altered serum lipoproteins (P< 0.01). Blue denotes low level in HBsAg (+) patients, and red denotes high level. Percent change = [CHBsAg (+)-CHBsAg (-)] /CHBsAg (-) × 100. C. Lipoproteins significantly associated with HBV-infection (Model 1), and adjusted with age, gender, hypertension, diabetes mellitus and coronary heart disease (Model 2). D. Lipoproteins significantly associated with HBV-infection in both differential analysis and logistic regression analysis (Model 2). VLDL— very low-density lipoprotein; IDL— intermediate-density lipoprotein; LDL—low-density lipoprotein; HDL— high-density lipoprotein; TAG— triacylglycerol; CH—cholesterol; FC—free cholesterol; CE—cholesterol esters; PL—phospholipids; PN—particle number.

Fig 1 Characteristics of changes in serum lipoproteins in HBsAg (+) and HBsAg (-) populations

图2 HBsAg(+) 和 HBsAg(-)人群中血清脂蛋白亚类及其组分与临床指标的相关性分析Note： A. Correlations of the 28 significantly changed lipoproteins with clinical parameters. Red boxes indicate positive correlation coefficient (r), and blue boxes, negative. **, P < 0.01; ***, P < 0.001. B. Linear correlation scatter plot.

Fig 2 Correlation analysis of serum lipoprotein subfractions and their components with clinical parameters in HBsAg (+) and HBsAg (-) populations

图3 血清脂蛋白能区分HBV患者Note： A. The ROC curves for HBV-infection. Five covariant included age, gender, hypertension, diabetes mellitus and coronary heart disease, and 6 lipoproteins included HDL4-PL, VLDL1-(PL/LP), VLDL1-(FC/LP), VLDL5-(TAG/LP), (VLDL+IDL)-PL and (VLDL+IDL)-TAG. B. 1H NMR signals for lipoproteins and their components. Red and blue lines represent HBsAg (-) and HBsAg (+) group, respectively. B. Lipoprotein metabolism associated with HBV-infection. LCAT—lecithin-cholesterol acyl transferase; CETP—cholesterol ester transfer protein; LPL—lipoprotein lipase; HTAGL—hepatic triacylglycerol lipase; LDLR—low-density lipoprotein receptor.

Fig 3 Lipoprotein phenotypes can differentiate HBV-infected patients from controls

参考文献 26

1	中华医学会感染病学分会, 中华医学会肝病学分会. 慢性乙型肝炎防治指南(2019年版)[J]. 中华肝脏病杂志, 2019, 27(12): 938-961.
	Chinese Society of Infectious Diseases Chinese Medical Association, Chinese Society of Hepatology Chinese Medical Association. The guidelines of prevention and treatment for chronic hepatitis B (2019 version)[J]. Chinese Journal of Hepatology, 2019, 27(12): 938-961.
2	MCGLYNN K A, PETRICK J L, EL-SERAG H B. Epidemiology of hepatocellular carcinoma[J]. Hepatology, 2021, 73(S1): 4-13.
3	LIU Z Q, JIANG Y F, YUAN H B, et al. The trends in incidence of primary liver cancer caused by specific etiologies: results from the Global Burden of Disease Study 2016 and implications for liver cancer prevention[J]. J Hepatol, 2019, 70(4): 674-683.
4	NGUYEN M H, WONG G, GANE E, et al. Hepatitis B virus: Advances in prevention, diagnosis, and therapy[J]. Clin Microbiol Rev, 2020, 33(2): e0046-e0019.
5	BAR-YISHAY I, SHAUL Y, SHLOMAI A. Hepatocyte metabolic signalling pathways and regulation of hepatitis B virus expression[J]. Liver Int, 2011, 31(3): 282-290.
6	HUANG Q X, LEI H H, DING L F, et al. Stimulated phospholipid synthesis is key for hepatitis B virus replications[J]. Sci Rep, 2019, 9(1): 12989.
7	JOO E J, CHANG Y, YEOM J S, et al. Hepatitis B virus infection and decreased risk of nonalcoholic fatty liver disease: a cohort study[J]. Hepatology, 2017, 65(3): 828-835.
8	WANG F B, ZHU C L, LIU X H, et al. HBV inhibits apoB production via the suppression of MTP expression[J]. Lipids Health Dis, 2011, 10: 207.
9	ZHU C L, GAO G S, SONG H, et al. Hepatitis B virus inhibits apolipoprotein A5 expression through its core gene[J]. Lipids Health Dis, 2016, 15(1): 178.
10	ZHU C L, ZHU H C, SONG H, et al. Hepatitis B virus inhibits the in vivo and in vitro synthesis and secretion of apolipoprotein C3[J]. Lipids Health Dis, 2017, 16(1): 213.
11	HSU C S, LIU C H, WANG C C, et al. Impact of hepatitis B virus infection on metabolic profiles and modifying factors[J]. J Viral Hepat, 2012, 19(2): E48-E57.
12	JAN C F, CHEN C J, CHIU Y H, et al. A population-based study investigating the association between metabolic syndrome and hepatitis B/C infection (Keelung Community-based Integrated Screening Study No. 10)[J]. Int J Obes (Lond), 2006, 30(5): 794-799.
13	QUAYE O, AMUZU B G, ADADEY S M, et al. Effect of hepatitis B virus (HBV) infection on lipid profile in Ghanaian patients[J]. Virology (Auckl), 2019, 10: 1178122X19827606.
14	TARGHER G, BERTOLINI L, PADOVANI R, et al. Differences and similarities in early atherosclerosis between patients with non-alcoholic steatohepatitis and chronic hepatitis B and C[J]. J Hepatol, 2007, 46(6): 1126-1132.
15	ZUO D, AN H H, LI J H, et al. The application value of lipoprotein particle numbers in the diagnosis of HBV-related hepatocellular carcinoma with BCLC stage 0-A[J]. J Pers Med, 2021, 11(11): 1143.
16	KULKARNI K R. Cholesterol profile measurement by vertical auto profile method[J]. Clin Lab Med, 2006, 26(4): 787-802.
17	RÁDIKOVÁ Ž, PENESOVÁ A, VLČEK M, et al. Lipoprotein profiling in early multiple sclerosis patients: effect of chronic inflammation?[J]. Lipids Health Dis, 2020, 19(1): 49.
18	KAUFMAN S L. Analysis of biomolecules using electrospray and nanoparticle methods: the gas-phase electrophoretic mobility molecular analyzer (GEMMA)[J]. J Aerosol Sci, 1998, 29(5/6): 537-552.
19	CLOUET-FORAISON N, GAIE-LEVREL F, GILLERY P, et al. Advanced lipoprotein testing for cardiovascular diseases risk assessment: a review of the novel approaches in lipoprotein profiling[J]. Clin Chem Lab Med, 2017, 55(10): 1453-1464.
20	JIMÉNEZ B, HOLMES E, HEUDE C, et al. Quantitative lipoprotein subclass and low molecular weight metabolite analysis in human serum and plasma by ¹H NMR spectroscopy in a multilaboratory trial [J]. Anal Chem, 2018, 90(20): 11962-11971.
21	YASUMOTO J, KASAI H, YOSHIMURA K, et al. Hepatitis B virus prevents excessive viral production via reduction of cell death-inducing DFF45-like effectors [J]. J Gen Virol, 2017, 98(7): 1762-1773.
22	ZHANG J X, LING N, LEI Y, et al. Multifaceted interaction between hepatitis B virus infection and lipid metabolism in hepatocytes: A potential target of antiviral therapy for chronic hepatitis B [J]. Front Microbiol, 2021, 12: 636897.
23	ARAIN S Q, TALPUR F N, CHANNA N A, et al. Serum lipids as an indicator for the alteration of liver function in patients with hepatitis B[J]. Lipids Health Dis, 2018, 17(1): 36.
24	OEHLER N, VOLZ T, BHADRA O D, et al. Binding of hepatitis B virus to its cellular receptor alters the expression profile of genes of bile acid metabolism[J]. Hepatology, 2014, 60(5): 1483-1493.
25	KONTUSH A, CHANTEPIE S, CHAPMAN M J. Small, dense HDL particles exert potent protection of atherogenic LDL against oxidative stress[J]. Arterioscler Thromb Vasc Biol, 2003, 23(10): 1881-1888.
26	HAN Y H, ONUFER E J, HUANG L H, et al. Enterically derived high-density lipoprotein restrains liver injury through the portal vein[J]. Science, 2021, 373(6553): eabe6729.

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乙型肝炎病毒感染者血清脂蛋白亚类及其组分的定量特征

Quantitative characteristics of serum lipoprotein phenotypes for HBV patients

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