肝因子和脂肪因子介导的脂代谢在非酒精性脂肪性肝病中的作用机制

赵晨露; 尚东方; 周铖; 石俊豪; 赵文霞

doi:10.3969/j.issn.1001-5256.2023.01.026

肝因子和脂肪因子介导的脂代谢在非酒精性脂肪性肝病中的作用机制

DOI: 10.3969/j.issn.1001-5256.2023.01.026

1.
河南中医药大学第一临床医学院，郑州 450000
2.
河南中医药大学第一附属医院脾胃肝胆科，郑州 450000

基金项目:

国家自然科学基金面上项目 (81473651);

河南省特色骨干学科中医学学科建设项目 (STG-ZYXKY-2020024)

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：赵晨露负责撰写论文；尚东方、周铖、石俊豪负责查阅、归纳文献；赵文霞负责指导撰写，修改论文。

详细信息

通信作者:
赵文霞, zhao-wenxia@163.com (ORCID: 0000-0002-0592-3504)

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- 被引次数: 0
出版历程
- 收稿日期: 2022-05-15
- 录用日期: 2022-07-06
- 出版日期: 2023-01-20

Mechanism of lipid metabolism mediated by hepatokines and adipokines in nonalcoholic fatty liver disease

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

Research funding:

National Natural Science Foundation Project （81473651）

Construction Project of Traditional Chinese Medicine Discipline in Henan Province （STG-ZYXKY-2020024）

More Information

Corresponding author: ZHAO Wenxia, zhao-wenxia@163.com (ORCID: 0000-0002-0592-3504)

摘要

摘要: 非酒精性脂肪性肝病(NAFLD)已更名为代谢相关脂肪性肝病，全身代谢功能障碍成为该病的关注点之一。NAFLD是以肝脏脂代谢紊乱为基础的代谢性疾病，与脂肪组织关系密切。肝脏和脂肪组织分泌的肝因子、脂肪因子在调节肝脏脂代谢方面具有重要作用。本文总结了具有促进或抑制脂代谢作用的肝因子和脂肪因子，重点关注了其介导的脂代谢在NAFLD中的作用机制，为临床防治提供思路和理论依据。
- 非酒精性脂肪性肝病 /
- 肝因子 /
- 脂肪因子类
Abstract: Nonalcoholic fatty liver disease (NAFLD) has been renamed as metabolic-associated fatty liver disease, and systemic metabolic dysfunction has become one of the concerns of this disease. NAFLD is a metabolic disease based on dyslipidemia in the liver, which is closely associated with adipose tissue. Hepatokines and adipokines secreted by the liver and adipose tissue play an important role in regulating liver lipid metabolism. This article summarizes the hepatokines and adipokines that can promote or inhibit lipid metabolism, focusing on the mechanism of lipid metabolism mediated by hepatokines and adipokines in NAFLD, so as to provides ideas and a theoretical basis for clinical prevention and treatment.
- Non-alcoholic Fatty Liver Disease /
- Hepatokines /
- Adipokines

HTML全文

图 1 肝脂质摄取与生产、输出与氧化示意图

注：HFD，高脂饮食；IR，胰岛素抵抗；ER，内质网；VLDL-TG，极低密度脂蛋白甘油三酯。

Figure 1. Liver lipid uptake and production, qutput and oxidation

下载: 全尺寸图片幻灯片

参考文献(57)

[1]	ZHOU J, ZHOU F, WANG W, et al. Epidemiological Features of NAFLD From 1999 to 2018 in China[J]. Hepatology, 2020, 71(5): 1851-1864. DOI: 10.1002/hep.31150.
[2]	LUNDBOM J. Adipose tissue and liver[J]. J Appl Physiol (1985), 2018, 124(1): 162-167. DOI: 10.1152/japplphysiol.00399.
[3]	LUUKKONEN PK, SÄEVIRTA S, ZHOU Y, et al. Saturated fat is more metabolically harmful for the human liver than unsaturated fat or simple sugars[J]. Diabetes Care, 2018, 41(8): 1732-1739. DOI: 10.2337/dc18-0071.
[4]	NIWA H, IIZUKA K, KATO T, et al. ChREBP rather than SHP regulates hepatic VLDL secretion[J]. Nutrients, 2018, 10(3): 321. DOI: 10.3390/nu10030321.
[5]	MONTAGNER A, POLIZZI A, FOUCHÉ E, et al. Liver PPARα is crucial for whole-body fatty acid homeostasis and is protective against NAFLD[J]. Gut, 2016, 65(7): 1202-1214. DOI: 10.1136/gutjnl-2015-310798.
[6]	MEEX R, WATT MJ. Hepatokines: linking nonalcoholic fatty liver disease and insulin resistance[J]. Nat Rev Endocrinol, 2017, 13(9): 509-520. DOI: 10.1038/nrendo.2017.56.
[7]	PIERANTONELLI I, SVEGLIATI-BARONI G. Nonalcoholic fatty liver disease: Basic pathogenetic mechanisms in the progression from NAFLD to NASH[J]. Transplantation, 2019, 103(1): e1-e13. DOI: 10.1097/TP.0000000000002480.
[8]	LIAN CY, ZHAI ZZ, LI ZF, et al. High fat diet-triggered non-alcoholic fatty liver disease: A review of proposed mechanisms[J]. Chem Biol Interact, 2020, 330: 109199. DOI: 10.1016/j.cbi.2020.109199.
[9]	YASKOLKA MEIR A, RINOTT E, TSABAN G, et al. Effect of green-Mediterranean diet on intrahepatic fat: the DIRECT PLUS randomised controlled trial[J]. Gut, 2021, 70(11): 2085-2095. DOI: 10.1136/gutjnl-2020-323106.
[10]	ABENAVOLI L, GRECO M, MILIC N, et al. Effect of mediterranean diet and antioxidant formulation in non-alcoholic fatty liver disease: A randomized study[J]. Nutrients, 2017, 9(8): 870. DOI: 10.3390/nu9080870.
[11]	TIMLIN MT, PARKS EJ. Temporal pattern of de novo lipogenesis in the postprandial state in healthy men[J]. Am J Clin Nutr, 2005, 81(1): 35-42. DOI: 10.1093/ajcn/81.1.35.
[12]	DONNELLY KL, SMITH CI, SCHWARZENBERG SJ, et al. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease[J]. J Clin Invest, 2005, 115(5): 1343-1351. DOI: 10.1172/JCI23621.
[13]	MATO JM, ALONSO C, NOUREDDIN M, et al. Biomarkers and subtypes of deranged lipid metabolism in non-alcoholic fatty liver disease[J]. World J Gastroenterol, 2019, 25(24): 3009-3020. DOI: 10.3748/wjg.v25.i24.3009.
[14]	FABBRINI E, MOHAMMED BS, MAGKOS F, et al. Alterations in adipose tissue and hepatic lipid kinetics in obese men and women with nonalcoholic fatty liver disease[J]. Gastroenterology, 2008, 134(2): 424-431. DOI: 10.1053/j.gastro.2007.11.038.
[15]	TOYODA Y, TAKADA T, YAMANASHI Y, et al. Pathophysiological importance of bile cholesterol reabsorption: hepatic NPC1L1-exacerbated steatosis and decreasing VLDL-TG secretion in mice fed a high-fat diet[J]. Lipids Health Dis, 2019, 18(1): 234. DOI: 10.1186/s12944-019-1179-0.
[16]	RADA P, GONZÁLEZ-RODRÍGUEZ Á, GARCÍA-MONZÓN C, et al. Understanding lipotoxicity in NAFLD pathogenesis: is CD36 a key driver?[J]. Cell Death Dis, 2020, 11(9): 802. DOI: 10.1038/s41419-020-03003-w.
[17]	CAO XF, DAI YJ, LIU MY, et al. High-fat diet induces aberrant hepatic lipid secretion in blunt snout bream by activating endoplasmic reticulum stress-associated IRE1/XBP1 pathway[J]. Biochim Biophys Acta Mol Cell Biol Lipids, 2019, 1864(3): 213-223. DOI: 10.1016/j.bbalip.2018.12.005.
[18]	QIN J, RU S, WANG W, et al. Long-term bisphenol S exposure aggravates non-alcoholic fatty liver by regulating lipid metabolism and inducing endoplasmic reticulum stress response with activation of unfolded protein response in male zebrafish[J]. Environ Pollut, 2020, 263(Pt B): 114535. DOI: 10.1016/j.envpol.2020.114535.
[19]	KUCUKOGLU O, SOWA JP, MAZZOLINI GD, et al. Hepatokines and adipokines in NASH-related hepatocellular carcinoma[J]. J Hepatol, 2021, 74(2): 442-457. DOI: 10.1016/j.jhep.2020.10.030.
[20]	ZORENA K, JACHIMOWICZ-DUDA O, S'LZAK D, et al. Adipokines and obesity. Potential link to metabolic disorders and chronic complications[J]. Int J Mol Sci, 2020, 21(10): 3570. DOI: 10.3390/ijms21103570.
[21]	YAN J, NIE Y, CAO J, et al. The roles and pharmacological effects of FGF21 in preventing aging-associated metabolic diseases[J]. Front Cardiovasc Med, 2021, 8: 655575. DOI: 10.3389/fcvm.2021.655575.
[22]	SCHLEIN C, TALUKDAR S, HEINE M, et al. FGF21 lowers plasma triglycerides by accelerating lipoprotein catabolism in white and brown adipose tissues[J]. Cell Metab, 2016, 23(3): 441-453. DOI: 10.1016/j.cmet.2016.01.006.
[23]	KONG Y, ZHAO C, TAN P, et al. FGF21 reduces lipid accumulation in bovine hepatocytes by enhancing lipid oxidation and reducing lipogenesis via AMPK signaling[J]. Animals (Basel), 2022, 12(7): 939. DOI: 10.3390/ani12070939.
[24]	RUSLI F, DEELEN J, ANDRIYANI E, et al. Fibroblast growth factor 21 reflects liver fat accumulation and dysregulation of signalling pathways in the liver of C57BL/6J mice[J]. Sci Rep, 2016, 6: 30484. DOI: 10.1038/srep30484.
[25]	ICER MA, Y_ILD_IRAN H. Effects of fetuin-A with diverse functions and multiple mechanisms on human health[J]. Clin Biochem, 2021, 88: 1-10. DOI: 10.1016/j.clinbiochem.2020.11.004.
[26]	PAN X, KAMINGA AC, CHEN J, et al. Fetuin-A and Fetuin-B in non-alcoholic fatty liver disease: A meta-analysis and meta-regression[J]. Int J Environ Res Public Health, 2020, 17(8): 2735. DOI: 10.3390/ijerph17082735.
[27]	SARDANA O, GOYAL R, BEDI O. Molecular and pathobiological involvement of fetuin-A in the pathogenesis of NAFLD[J]. Inflammopharmacology, 2021, 29(4): 1061-1074. DOI: 10.1007/s10787-021-00837-4.
[28]	LU CW, LEE YC, CHIANG CH, et al. Independent dose-response associations between Fetuin-A and lean nonalcoholic fatty liver disease[J]. Nutrients, 2021, 13(9): 2928. DOI: 10.3390/nu13092928.
[29]	SHIM YS, KANG MJ, OH YJ, et al. Fetuin-A as an alternative marker for insulin resistance and cardiovascular risk in prepubertal children[J]. J Atheroscler Thromb, 2017, 24(10): 1031-1038. DOI: 10.5551/jat.38323.
[30]	KAHRAMAN A, SOWA JP, SCHLATTJAN M, et al. Fetuin-A mRNA expression is elevated in NASH compared with NAFL patients[J]. Clin Sci (Lond), 2013, 125(8): 391-400. DOI: 10.1042/CS20120542.
[31]	MULARCZYK M, BOUREBABA Y, KOWALCZUK A, et al. Probiotics-rich emulsion improves insulin signalling in Palmitate/Oleate-challenged human hepatocarcinoma cells through the modulation of Fetuin-A/TLR4-JNK-NF-κB pathway[J]. Biomed Pharmacother, 2021, 139: 111560. DOI: 10.1016/j.biopha.2021.111560.
[32]	JIANG S, QIU GH, ZHU N, et al. ANGPTL3: a novel biomarker and promising therapeutic target[J]. J Drug Target, 2019, 27(8): 876-884. DOI: 10.1080/1061186X.2019.1566342.
[33]	CHRISTOPOULOU E, ELISAF M, FILIPPATOS T. Effects of angiopoietin-like 3 on triglyceride regulation, glucose homeostasis, and diabetes[J]. Dis Markers, 2019, 2019: 6578327. DOI: 10.1155/2019/6578327.
[34]	YILMAZ Y, ULUKAYA E, ATUG O, et al. Serum concentrations of human angiopoietin-like protein 3 in patients with nonalcoholic fatty liver disease: association with insulin resistance[J]. Eur J Gastroenterol Hepatol, 2009, 21(11): 1247-1251. DOI: 10.1097/MEG.0b013e32832b77ae.
[35]	KE Y, LIU S, ZHANG Z, et al. Circulating angiopoietin-like proteins in metabolic-associated fatty liver disease: a systematic review and meta-analysis[J]. Lipids Health Dis, 2021, 20(1): 55. DOI: 10.1186/s12944-021-01481-1.
[36]	BARCHETTA I, CIMINI FA, CHIAPPETTA C, et al. Relationship between hepatic and systemic angiopoietin-like 3, hepatic Vitamin D receptor expression and NAFLD in obesity[J]. Liver Int, 2020, 40(9): 2139-2147. DOI: 10.1111/liv.14554.
[37]	CHEN Y, HE X, CHEN X, et al. SeP is elevated in NAFLD and participates in NAFLD pathogenesis through AMPK/ACC pathway[J]. J Cell Physiol, 2021, 236(5): 3800-3807. DOI: 10.1002/jcp.30121.
[38]	CHOI HY, HWANG SY, LEE CH, et al. Increased selenoprotein p levels in subjects with visceral obesity and nonalcoholic Fatty liver disease[J]. Diabetes Metab J, 2013, 37(1): 63-71. DOI: 10.4093/dmj.2013.37.1.63.
[39]	POLYZOS SA, KOUNTOURAS J, MAVROULI M, et al. Selenoprotein P in patients with nonalcoholic fatty liver disease[J]. Exp Clin Endocrinol Diabetes, 2019, 127(9): 598-602. DOI: 10.1055/a-0811-9136.
[40]	YILMAZ Y, YONAL O, KURT R, et al. Serum levels of omentin, chemerin and adipsin in patients with biopsy-proven nonalcoholic fatty liver disease[J]. Scand J Gastroenterol, 2011, 46(1): 91-97. DOI: 10.3109/00365521.2010.516452.
[41]	KAJOR M, KUKLA M, WALUGA M, et al. Hepatic chemerin mRNA in morbidly obese patients with nonalcoholic fatty liver disease[J]. Pol J Pathol, 2017, 68(2): 117-127. DOI: 10.5114/pjp.2017.69687.
[42]	KUKLA M, ZWIRSKA-KORCZALA K, HARTLEB M, et al. Serum chemerin and vaspin in non-alcoholic fatty liver disease[J]. Scand J Gastroenterol, 2010, 45(2): 235-242. DOI: 10.3109/00365520903443852.
[43]	POHL R, HABERL EM, REIN-FISCHBOECK L, et al. Hepatic chemerin mRNA expression is reduced in human nonalcoholic steatohepatitis[J]. Eur J Clin Invest, 2017, 47(1): 7-18. DOI: 10.1111/eci.12695.
[44]	AN X, LIU J, LI Y, et al. Chemerin/CMKLR1 ameliorates nonalcoholic steatohepatitis by promoting autophagy and alleviating oxidative stress through the JAK2-STAT3 pathway[J]. Peptides, 2021, 135: 170422. DOI: 10.1016/j.peptides.2020.170422.
[45]	MISHRA I, DUERRSCHMID C, KU Z, et al. Asprosin-neutralizing antibodies as a treatment for metabolic syndrome[J]. Elife, 2021, 10. DOI: 10.7554/eLife.63784.
[46]	ZHANG Y, ZHU Z, ZHAI W, et al. Expression and purification of asprosin in Pichia pastoris and investigation of its increase glucose uptake activity in skeletal muscle through activation of AMPK[J]. Enzyme Microb Technol, 2021, 144: 109737. DOI: 10.1016/j.enzmictec.2020.109737.
[47]	LI E, SHAN H, CHEN L, et al. OLFR734 mediates glucose metabolism as a receptor of asprosin[J]. Cell Metab, 2019, 30(2): 319-328. e8. DOI: 10.1016/j.cmet.2019.05.022.
[48]	HEKIM MG, KELESTEMUR MM, BULMUS FG, et al. Asprosin, a novel glucogenic adipokine: a potential therapeutic implication in diabetes mellitus[J]. Arch Physiol Biochem, 2021: 1-7. DOI: 10.1080/13813455.2021.1894178.
[49]	LIU LJ, KANG YR, XIAO YF. Increased asprosin is associated with non-alcoholic fatty liver disease in children with obesity[J]. World J Pediatr, 2021, 17(4): 394-399. DOI: 10.1007/s12519-021-00444-x.
[50]	LI H, ZHANG Y, WANG F, et al. Effects of irisin on the differentiation and browning of human visceral white adipocytes[J]. Am J Transl Res, 2019, 11(12): 7410-7421.
[51]	CHEN Y, DING J, ZHAO Y, et al. Irisin induces white adipose tissue browning in mice as assessed by magnetic resonance imaging[J]. Exp Biol Med (Maywood), 2021, 246(14): 1597-1606. DOI: 10.1177/15353702211006049.
[52]	ZHANG Y, LI R, MENG Y, et al. Irisin stimulates browning of white adipocytes through mitogen-activated protein kinase p38 MAP kinase and ERK MAP kinase signaling[J]. Diabetes, 2014, 63(2): 514-525. DOI: 10.2337/db13-1106.
[53]	TSAI YC, WANG CW, WEN BY, et al. Involvement of the p62/Nrf2/HO-1 pathway in the browning effect of irisin in 3T3-L1 adipocytes[J]. Mol Cell Endocrinol, 2020, 514: 110915. DOI: 10.1016/j.mce.2020.110915.
[54]	HU J, KE Y, WU F, et al. Circulating irisin levels in patients with nonalcoholic fatty liver disease: A systematic review and meta-analysis[J]. Gastroenterol Res Pract, 2020, 2020: 8818191. DOI: 10.1155/2020/8818191.
[55]	ZHANG HJ, ZHANG XF, MA ZM, et al. Irisin is inversely associated with intrahepatic triglyceride contents in obese adults[J]. J Hepatol, 2013, 59(3): 557-562. DOI: 10.1016/j.jhep.2013.04.030.
[56]	VIITASALO A, ATALAY M, PIHLAJAMÄKI J, et al. The 148 M allele of the PNPLA3 is associated with plasma irisin levels in a population sample of Caucasian children: The PANIC Study[J]. Metabolism, 2015, 64(7): 793-796. DOI: 10.1016/j.metabol.2015.01.010.
[57]	MEDHAT D, EL-BANA MA, EL-DALY SM, et al. Influence of irisin on diet-induced metabolic syndrome in experimental rat model[J]. J Complement Integr Med, 2021, 18(2): 347-354. DOI: 10.1515/jcim-2020-0030.