影响鸡脂肪肝出血综合征的因素及“多重打击”学说

doi:10.11843/j.issn.0366-6964.2022.08.005

摘要/Abstract

摘要： 鸡脂肪肝出血综合征（fatty liver hemorrhagic syndrome，FLHS）是笼养鸡非感染性死亡的主要原因之一，以肝组织质脆、破裂出血、突然死亡为主要特征。鸡由于其生理特性较哺乳动物更易形成FLHS，但鸡FLHS发病机制尚未明确。本文将从FLHS疾病发生的多重影响因素如遗传、营养、激素、环境、肠道微生物等方面进行阐述，列举和对比研究人员通过改变鸡饲粮成分或使用激素等构建FLHS模型的方法，提出“多重打击”学说的发病机制，以期为鸡FLHS研究提供一定的参考。

关键词: 鸡脂肪肝出血综合征, 影响因素, 模型, "多重打击"学说

Abstract: Fatty liver hemorrhagic syndrome (FLHS) is one of the main causes of noninfectious death in cage chickens. It is characterized by fragile liver, rupture bleeding and sudden death. Chicken is easier to form FLHS than mammals because of its physiological characteristics,but the pathogenesis of chicken FLHS is not clear. This paper will elaborate the multiple influencing factors of FLHS disease, such as genetics, nutrition, hormones, environment and intestinal microorganisms. Enumerating and comparing the way of structuring FLHS model by changing diet composition or hormones, and putting forward the pathogenesis of "the multiple-hit" pathogenesis in order to provide a reference for further study of chicken FLHS.

Key words: chicken fatty liver hemorrhagic syndrome, influencing factors, models, the multiple-hit pathogenesis

中图分类号:

S856.4

张弥, 涂闻君, 张奇, 江莎. 影响鸡脂肪肝出血综合征的因素及“多重打击”学说[J]. 畜牧兽医学报, 2022, 53(8): 2453-2469.

ZHANG Mi, TU Wenjun, ZHANG Qi, JIANG Sha. The Influencing Factors and the Multiple-hit Pathogenesis of Chicken Fatty Liver Hemorrhagic Syndrome[J]. Acta Veterinaria et Zootechnica Sinica, 2022, 53(8): 2453-2469.

参考文献 155

[1]	ROZENBOIM I, MAHATO J, COHEN N A, et al.Low protein and high-energy diet:A possible natural cause of fatty liver hemorrhagic syndrome in caged White Leghorn laying hens[J].Poult Sci, 2016, 95(3):612-621.
[2]	MENG J, MA N, LIU H, et al. Untargeted and targeted metabolomics profiling reveals the underlying pathogenesis and abnormal arachidonic acid metabolism in laying hens with fatty liver hemorrhagic syndrome[J]. Poult Sci, 2021, 100(9):101320.
[3]	TROTT K A, GIANNITTI F, RIMOLDI G, et al.Fatty liver hemorrhagic syndrome in the backyard chicken:A retrospective histopathologic case series[J].Vet Pathol, 2014, 51(4):787-795.
[4]	CHEN W, SHI Y, LI G, et al. Preparation of the peroxisome proliferator-activated receptor α polyclonal antibody:Its application in fatty liver hemorrhagic syndrome[J].Int J Bio Macromol, 2021, 182:179-186.
[5]	WU X L, ZOU X Y, ZHANG M, et al.Osteocalcin prevents insulin resistance, hepatic inflammation, and activates autophagy associated with high-fat diet-induced fatty liver hemorrhagic syndrome in aged laying hens[J].Poult Sci, 2021, 100(1):73-83.
[6]	ABPLANALP H, NAPOLITANO D J P S.Genetic predisposition for fatty liver ruptures in White Leghorn hens of a highly inbred line[J].Poult Sci, 1987, 66(S1):52.
[7]	ZHANG Y H, LIU Z, LIU R R, et al.Alteration of hepatic gene expression along with the inherited phenotype of acquired fatty liver in chicken[J].Genes, 2018, 9(4):199.
[8]	ESLAM M, VALENTI L, ROMEO S.Genetics and epigenetics of NAFLD and NASH:clinical impact[J].J Hepatol, 2018, 68(2):268-279.
[9]	TAN X D, LIU R R, ZHANG Y H, et al.Integrated analysis of the methylome and transcriptome of chickens with fatty liver hemorrhagic syndrome[J].BMC Genomics, 2021, 22(1):8.
[10]	LIU Z, LI Q H, LIU R R, et al.Expression and methylation of microsomal triglyceride transfer protein and acetyl-CoA carboxylase are associated with fatty liver syndrome in chicken[J].Poult Sci, 2016, 95(6):1387-1395.
[11]	LI H, GU Z, YANG L, et al.Transcriptome profile analysis reveals an estrogen induced LncRNA associated with lipid metabolism and carcass traits in chickens (Gallus Gallus)[J].Cell Physiol Biochem, 2018, 50(5):1638-1658.
[12]	TAN X D, LIU R R, XING S Y, et al.Genome-wide detection of key genes and epigenetic markers for chicken fatty liver[J].Int J Mol Sci, 2020, 21(5):1800.
[13]	ZHU Y L, ZENG Q J, LI F, et al.Dysregulated H3K27 acetylation is implicated in fatty liver hemorrhagic syndrome in chickens[J].Front Genet, 2021, 11:574167.
[14]	HERMIER D.Lipoprotein metabolism and fattening in poultry[J].J Nutr, 1997, 127(S5):805S-808S.
[15]	LEVEILLE G A, ROMSOS D R, YEH Y Y, et al.Lipid biosynthesis in the chick.A consideration of site of synthesis, influence of diet and possible regulatory mechanisms[J].Poult Sci, 1975, 54(4):1075-1093.
[16]	YANG J C Z, FERNÁNDEZ-GALILEA M, MARTÍNEZ-FERNÁNDEZ L, et al.Oxidative stress and non-alcoholic fatty liver disease:Effects of omega-3 fatty acid supplementation[J].Nutrients, 2019, 11(4):872.
[17]	YKI-JÄRVINEN H.Nutritional modulation of non-alcoholic fatty liver disease and insulin resistance[J].Nutrients, 2015, 7(11):9127-9138.
[18]	AL-KHALAIFAH H, AL-NASSER A, GIVENS D I, et al.Comparison of different dietary sources of n-3 polyunsaturated fatty acids on immune response in broiler chickens[J].Heliyon, 2020, 6(1):e03326.
[19]	SHAMA S, LIU W Q.Omega-3 fatty acids and gut microbiota:A reciprocal interaction in nonalcoholic fatty liver disease[J].Dig Dis Sci, 2020, 65(3):906-910.
[20]	NEIJAT M, HABTEWOLD J, LI S, et al.Effect of dietary n-3 polyunsaturated fatty acids on the composition of cecal microbiome of Lohmann hens[J].Prostaglandins Leukot Essent Fatty Acids, 2020, 162:102182.
[21]	GUO L Y, KUANG J, ZHUANG Y, et al.Serum metabolomic profiling to reveal potential biomarkers for the diagnosis of fatty liver hemorrhagic syndrome in laying hens[J].Front Physiol, 2021, 12:590638.
[22]	AN Y P, XU W X, LI H H, et al.High-fat diet induces dynamic metabolic alterations in multiple biological matrices of rats[J].J Proteome Res, 2013, 12(8):3755-3768.
[23]	FU C Y, ZHANG Y, YAO Q M, et al.Maternal conjugated linoleic acid alters hepatic lipid metabolism via the AMPK signaling pathway in chick embryos[J].Poult Sci, 2020, 99(1):224-234.
[24]	JAENISCH R, BIRD A.Epigenetic regulation of gene expression:how the genome integrates intrinsic and environmental signals[J].Nat Genet, 2003, 33 Suppl 1:245-254.
[25]	DONG X F, ZHAI Q H, TONG J M.Dietary choline supplementation regulated lipid profiles of egg yolk, blood, and liver and improved hepatic redox status in laying hens[J].Poult Sci, 2019, 98(8):3304-3312.
[26]	HU Y, SUN Q W, HU Y, et al.Corticosterone-induced lipogenesis activation and lipophagy inhibition in chicken liver are alleviated by maternal betaine supplementation[J].J Nutr, 2018, 148(3):316-325.
[27]	ALAGAWANY M, ELNESR S S, FARAG M R, et al.Nutritional significance of amino acids, vitamins and minerals as nutraceuticals in poultry production and health-a comprehensive review[J].Vet Q, 2020, 41(1):1-29.
[28]	YANG F, RUAN J M, WANG T C, et al.Improving effect of dietary soybean phospholipids supplement on hepatic and serum indexes relevant to fatty liver hemorrhagic syndrome in laying hens[J].Anim Sci J, 2017, 88(11):1860-1869.
[29]	SONG Y L, RUAN J M, LUO J R, et al.Abnormal histopathology, fat percent and hepatic apolipoprotein A I and apolipoprotein B100 mRNA expression in fatty liver hemorrhagic syndrome and their improvement by soybean lecithin[J].Poult Sci, 2017, 96(10):3559-3563.
[30]	REN Z H, DENG H D, DENG Y T, et al.Effects of selenium on arsenic-induced liver lesions in broilers[J].Biol Trace Elem Res, 2021, 199(3):1080-1089.
[31]	ZHUANG Y, XING C H, CAO H B, et al.Insulin resistance and metabonomics analysis of fatty liver haemorrhagic syndrome in laying hens induced by a high-energy low-protein diet[J].Sci Rep, 2019, 9(1):10141.
[32]	BELLO A, DERSJANT-LI Y, KORVER D R.Effects of dietary calcium and available phosphorus levels and phytase supplementation on performance, bone mineral density, and serum biochemical bone markers in aged white egg-laying hens[J].Poult Sci, 2020, 99(11):5792-5801.
[33]	SHOJADOOST B, YITBAREK A, ALIZADEH M, et al.Centennial review:Effects of vitamins A, D, E, and C on the chicken immune system[J].Poult Sci, 2021, 100(4):100930.
[34]	SHINI A, SHINI S, BRYDEN W L.Fatty liver haemorrhagic syndrome occurrence in laying hens:impact of production system[J].Avian Pathol, 2019, 48(1):25-34.
[35]	PEARSON A W, CURTIS M J, BUTLER E J.Bacterial endotoxins and the pathogenesis of fatty liver-haemorrhagic syndrome in the laying hen[J].Res Vet Sci, 1981, 31(2):259-261.
[36]	EMAMI N K, JUNG U, VOY B, et al.Radical response:effects of heat stress-induced oxidative stress on lipid metabolism in the avian liver[J].Antioxidants (Basel), 2020, 10(1):35.
[37]	LU Z, HE X F, MA B B, et al.Increased fat synthesis and limited apolipoprotein B cause lipid accumulation in the liver of broiler chickens exposed to chronic heat stress[J].Poult Sci, 2019, 98(9):3695-3704.
[38]	PALMISANO B T, ZHU L, STAFFORD J M.Role of estrogens in the regulation of liver lipid metabolism[J].Adv Exp Med Biol, 2017, 1043:227-256.
[39]	YANG L Y, LIU Z M, OU K P, et al.Evolution, dynamic expression changes and regulatory characteristics of gene families involved in the glycerophosphate pathway of triglyceride synthesis in chicken (Gallus gallus)[J].Sci Rep, 2019, 9(1):12735.
[40]	SHINI S, SHINI A, BRYDEN W L.Unravelling fatty liver haemorrhagic syndrome:1.Oestrogen and inflammation[J].Avian Pathol, 2020, 49(1):87-98.
[41]	SHINI S, SHINI A, BRYDEN W L.Unravelling fatty liver haemorrhagic syndrome:2.Inflammation and pathophysiology[J].Avian Pathol, 2020, 49(2):131-143.
[42]	DONG X, TONG J.Different susceptibility to fatty liver-haemorrhagic syndrome in young and older layers and the interaction on blood LDL-C levels between oestradiols and high energy-low protein diets[J].Br Poult Sci, 2019, 60(3):265-271.
[43]	HU Y, FENG Y, ZHANG L C, et al.GR-mediated FTO transactivation induces lipid accumulation in hepatocytes via demethylation of m6A on lipogenic mRNAs[J].RNA Biol, 2020, 17(7):930-942.
[44]	HU X Y, CAI Y L, KONG L L, et al.Effects of dietary corticosterone on the central adenosine monophosphate-activated protein kinase (AMPK) signaling pathway in broiler chickens[J].J Anim Sci, 2020, 98(7):skaa202.
[45]	FENG Y, HU Y, HOU Z, et al.Chronic corticosterone exposure induces liver inflammation and fibrosis in association with m6A-linked post-transcriptional suppression of heat shock proteins in chicken[J].Cell Stress Chaperones, 2020, 25(1):47-56.
[46]	HU X Y, WANG Y F, SHEIKHAHMADI A, et al.Effects of glucocorticoids on lipid metabolism and AMPK in broiler chickens' liver[J].Comp Biochem Physiol Part B:Biochem Mol Biol, 2019, 232:23-30.
[47]	FILIP R, RADZKI R P, BIEŃKO M.Novel insights into the relationship between nonalcoholic fatty liver disease and osteoporosis[J].Clin Interv Aging, 2018, 13:1879-1891.
[48]	XIA M F, RONG S X, ZHU X P, et al.Osteocalcin and non-alcoholic fatty liver disease:Lessons from two population-based cohorts and animal models[J].J Bone Miner Res, 2021, 36(4):712-728.
[49]	ZHANG M L, NIE X M, YUAN Y Q, et al.Osteocalcin alleviates nonalcoholic fatty liver disease in mice through GPRC6A[J].Int J Endocrinol, 2021, 2021:9178616.
[50]	JIANG S, CHENG H W, CUI L Y, et al.Changes of blood parameters associated with bone remodeling following experimentally induced fatty liver disorder in laying hens[J].Poult Sci, 2013, 92(6):1443-1453.
[51]	TANG Q Y, LI W T, DAI N, et al.The role of necroptosis, apoptosis, and inflammation in fowl cholera-associated liver injury in a chicken model[J].Avian Dis, 2017, 61(4):491-502.
[52]	HAN B, LV Z J, ZHANG X Y, et al.Deltamethrin induces liver fibrosis in quails via activation of the TGF-β1/Smad signaling pathway[J].Environ Pollut, 2020, 259:113870.
[53]	SIMON V, SREERAG K V, SASIKUMAR R, et al.In vitro protective effect of ascorbic acid against antibiotic-induced hepatotoxicity[J].Curr Durg Discov Technol, 2020, 17(3):357-364.
[54]	RASHIDI N, KHATIBJOO A, TAHERPOUR K, et al.Effects of licorice extract, probiotic, toxin binder and poultry litter biochar on performance, immune function, blood indices and liver histopathology of broilers exposed to aflatoxin-B1[J].Poult Sci, 2020, 99(11):5896-5906.
[55]	LIU X Q, MISHRA S K, WANG T, et al.AFB1 induced transcriptional regulation related to apoptosis and lipid metabolism in liver of chicken[J].Toxins, 2020, 12(5):290.
[56]	HUA Z L, LIU R, CHEN Y W, et al.Contamination of aflatoxins induces severe hepatotoxicity through multiple mechanisms[J].Front Pharmacol, 2020, 11:605823.
[57]	FAN T T, XIE Y L, MA W B.Research progress on the protection and detoxification of phytochemicals against aflatoxin B1-Induced liver toxicity[J].Toxicon, 2021, 195:58-68.
[58]	GO Y M, SUTLIFF R L, CHANDLER J D, et al.Low-dose cadmium causes metabolic and genetic dysregulation associated with fatty liver disease in mice[J].Toxicol Sci, 2015, 147(2):524-534.
[59]	ALSHEHRI A S, EL-KOTT A F, EL-KENAWY A E, et al.Cadmium chloride induces non-alcoholic fatty liver disease in rats by stimulating miR-34a/SIRT1/FXR/p53 axis[J].Sci Total Environ, 2021, 784:147182.
[60]	ZHU M K, LI H Y, BAI L H, et al.Histological changes, lipid metabolism, and oxidative and endoplasmic reticulum stress in the liver of laying hens exposed to cadmium concentrations[J].Poult Sci, 2020, 99(6):3215-3228.
[61]	HU H M, LIN A Z, KONG M W, et al.Intestinal microbiome and NAFLD:molecular insights and therapeutic perspectives[J].J Gastroenterol, 2020, 55(2):142-158.
[62]	LI S, YAN C C, LIU T J, et al.Research Note:Increase of bad bacteria and decrease of good bacteria in the gut of layers with vs. without hepatic steatosis[J].Poult Sci, 2020, 99(10):5074-5078.
[63]	HAMID H, ZHANG J Y, LI W X, et al.Interactions between the cecal microbiota and non-alcoholic steatohepatitis using laying hens as the model[J].Poult Sci, 2019, 98(6):2509-2521.
[64]	KALAVATHY R, ABDULLAH N, JALALUDIN S, et al.Effects of Lactobacillus feed supplementation on cholesterol, fat content and fatty acid composition of the liver, muscle and carcass of broiler chickensl[J].Anim Res, 2006, 55(1):77-82.
[65]	YALÇIN S, GÜÇER K Ş, YALÇIN S, et al.Effects of probiotic (Primalac 454) on nonalcoholic fatty liver disease in broilers[J].Revue Méd Vét, 2011, 162(7):371-376.
[66]	ZHANG J M, SUN Y S, ZHAO L Q, et al.SCFAs-induced GLP-1 secretion links the regulation of gut microbiome on hepatic lipogenesis in chickens[J].Front Microbiol, 2019, 10:2176.
[67]	MARTÍN-CASTILLO A, CASTELLS M T, ADÁNEZ G, et al.Effect of atorvastatin and diet on non-alcoholic fatty liver disease activity score in hyperlipidemic chickens[J].Biomed Pharmacother, 2010, 64(4):275-281.
[68]	SÁNCHEZ-POLO M T, CASTELLS M T, GARCÍA-PÉREZ B, et al.Effect of diet/atorvastatin on atherosclerotic lesions associated to nonalcoholic fatty liver disease in chickens[J].Histol Histopathol, 2015, 30(12):1439-1446.
[69]	QIU K, ZHAO Q, WANG J, et al.Effects of pyrroloquinoline quinone on lipid metabolism and anti-oxidative capacity in a high-fat-diet metabolic dysfunction-associated fatty liver disease chick model[J].Int J Mol Sci, 2021, 22(3):1458.
[70]	CHOI Y I, AHN H J, LEE B K, et al.Nutritional and hormonal induction of fatty liver syndrome and effects of dietary lipotropic factors in egg-type male chicks[J].Asian-Australas J Anim Sci, 2012, 25(8):1145-1152.
[71]	SHINI S, BRYDEN W L.Occurrence and control of fatty liver haemorrhagic syndrome (FLHS) in caged hens[J].Sci Rep, 2009, 1448-1316.
[72]	POLIN D, WOLFORD J H.Role of estrogen as a cause of fatty liver hemorrhagic syndrome[J].J Nutr, 1977, 107(5):873-886.
[73]	POLIN D, WOLFORD J H.Various types of diets, sources of energy, and positive energy balance in the induction of fatty liver hemorrhagic syndrome[J].Poult Sci, 1976, 55(1):325-334.
[74]	HAGHIGHI-RAD F, POLIN D.Lipid alleviates fatty liver hemorrhagic syndrome[J].Poult Sci, 1982, 61(12):2465-2472.
[75]	ZHU Y L, MAO H R, PENG G, et al.Effect of JAK-STAT pathway in regulation of fatty liver hemorrhagic syndrome in chickens[J].Anim Biosci, 2021, 34(1):143-153.
[76]	PENG G, HUANG E F, RUAN J M, et al.Effects of a high energy and low protein diet on hepatic and plasma characteristics and Cidea and Cidec mRNA expression in liver and adipose tissue of laying hens with fatty liver hemorrhagic syndrome[J].Anim Sci J, 2019, 90(2):247-254.
[77]	ZHANG J W, CHEN D W, YU B.Effect of different dietary energy sources on induction of fatty liver-hemorrhagic syndrome in laying hens[J].Int J Poult Sci, 2008, 7(12):1232-1236.
[78]	MOHAMMADPOUR F, DARMANI-KUHI H, MOHIT A, et al.Obesity, insulin resistance, adiponectin, and PPAR-γ gene expression in broiler chicks fed diets supplemented with fat and green tea (Camellia sinensis) extract[J].Domest Anim Endocrinol, 2020, 72:106440.
[79]	XING C H, WANG Y, DAI X Y, et al.The protective effects of resveratrol on antioxidant function and the mRNA expression of inflammatory cytokines in the ovaries of hens with fatty liver hemorrhagic syndrome[J].Poult Sci, 2020, 99(2):1019-1027.
[80]	YOUSEFI M, SHIVAZAD M, SOHRABI-HAGHDOOST I.Effect of dietary factors on induction of fatty liver-hemorrhagic syndrome and its diagnosis methods with use of serum and liver parameters in laying hens[J].Int J Poult Sci, 2005, 4(8):568-572.
[81]	LIN C W, HUANG T W, PENG Y J, et al.A novel chicken model of fatty liver disease induced by high cholesterol and low choline diets[J].Poult Sci, 2021, 100(3):100869.
[82]	CHEN C Y, CHEN Y J, DING S T, et al.Expression profile of adiponectin and adiponectin receptors in high-fat diet feeding chickens[J].J Anim Physiol Anim Nutr (Berl), 2018, 102(6):1585-1592.
[83]	MIAO Y F, GAO X N, XU D N, et al.Protective effect of the new prepared Atractylodes macrocephala Koidz polysaccharide on fatty liver hemorrhagic syndrome in laying hens[J].Poult Sci, 2021, 100(2):938-948.
[84]	GAO X N, LIU P, WU C, et al.Effects of fatty liver hemorrhagic syndrome on the AMP-activated protein kinase signaling pathway in laying hens[J].Poult Sci, 2019, 98(5):2201-2210.
[85]	WANG X Y, XING C H, YANG F, et al.Abnormal expression of liver autophagy and apoptosis-related mRNA in fatty liver haemorrhagic syndrome and improvement function of resveratrol in laying hens[J].Avian Pathol, 2020, 49(2):171-178.
[86]	BUZZETTI E, PINZANI M, TSOCHATZIS E A.The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD)[J].Metabolism, 2016, 65(8):1038-1048.
[87]	CHIU S, MULLIGAN K, SCHWARZ J M.Dietary carbohydrates and fatty liver disease:de novo lipogenesis[J].Curr Opin Clin Nutr Metab Care, 2018, 21(4):277-282.
[88]	ALKHOURI N, LAWITZ E, NOUREDDIN M, et al.GS-0976 (Firsocostat):An investigational liver-directed acetyl-CoA carboxylase (ACC) inhibitor for the treatment of non-alcoholic steatohepatitis (NASH)[J].Expert Opin Investig Drugs, 2020, 29(2):135-141.
[89]	SYED-ABDUL M M, PARKS E J, GABALLAH A H, et al.Fatty acid synthase inhibitor TVB-2640 reduces hepatic de novo lipogenesis in males with metabolic abnormalities[J].Hepatology, 2020, 72(1):103-118.
[90]	BECARES N, GAGE M C, VOISIN M, et al.Impaired LXRα phosphorylation attenuates progression of fatty liver disease[J].Cell Rep, 2019, 26(4):984-995.e6.
[91]	KERSTEN S, STIENSTRA R.The role and regulation of the peroxisome proliferator activated receptor alpha in human liver[J].Biochimie, 2017, 136:75-84.
[92]	ZHANG L J, LI C Y, WANG F, et al.Treatment with PPARα agonist clofibrate inhibits the transcription and activation of SREBPs and reduces triglyceride and cholesterol levels in liver of broiler chickens[J].PPAR Res, 2015, 2015:347245.
[93]	ZHANG K, SHI Y, HUANG C L, et al.Activation of AMP-activated protein kinase signaling pathway ameliorates steatosis in laying hen hepatocytes[J].Poult Sci, 2021, 100(3):100805.
[94]	FENG S Q, WANG H, WANG Y, et al.Apatinib induces 3-hydroxybutyric acid production in the liver of mice by peroxisome proliferator-activated receptor α activation to aid its antitumor effect[J].Cancer Sci, 2019, 110(10):3328-3339.
[95]	YANG M, LIU Q L, HUANG T L, et al.Dysfunction of estrogen-related receptor alpha-dependent hepatic VLDL secretion contributes to sex disparity in NAFLD/NASH development[J].Theranostics, 2020, 10(24):10874-10891.
[96]	DUPONT J, TESSERAUD S, SIMON J.Insulin signaling in chicken liver and muscle[J].Gen Comp Endocrinol, 2009, 163(1-2):52-57.
[97]	DUPONT J, TESSERAUD S, DEROUET M, et al.Insulin immuno-neutralization in chicken:Effects on insulin signaling and gene expression in liver and muscle[J].J Endocrinol, 2008, 197(3):531-542.
[98]	DUPONT J, MÉTAYER-COUSTARD S, JI B, et al.Characterization of major elements of insulin signaling cascade in chicken adipose tissue:apparent insulin refractoriness[J].Gen Comp Endocrinol, 2012, 176(1):86-93.
[99]	BRAUN E J, SWEAZEA K L.Glucose regulation in birds[J].Comp Biochem Physiol B:Biochem Mol Biol, 2008, 151(1):1-9.
[100]	BODEN G.Obesity, insulin resistance and free fatty acids[J].Curr Opin Endocrinol, Diabetes Obes, 2011, 18(2):139-143.
[101]	YAZICI D, SEZER H.Insulin resistance, obesity and lipotoxicity[J].Adv Exp Med Biol, 2017, 960:277-304.
[102]	SHETTY S S, KUMARI S.Fatty acids and their role in type-2 diabetes (Review)[J].Exp Ther Med, 2021, 22(1):706.
[103]	YUNG J H M, GIACCA A.Role of c-jun N-terminal kinase (JNK) in obesity and type 2 diabetes[J].Cells, 2020, 9(3):706.
[104]	SMITH G I, SHANKARAN M, YOSHINO M, et al.Insulin resistance drives hepatic de novo lipogenesis in nonalcoholic fatty liver disease[J].J Clin Invest, 2020, 130(3):1453-1460.
[105]	SCHENKEL L C, BAKOVIC M.Formation and regulation of mitochondrial membranes[J].Int J Cell Biol, 2014, 2014:709828.
[106]	WANG J, HE W P, TSAI P J, et al.Mutual interaction between endoplasmic reticulum and mitochondria in nonalcoholic fatty liver disease[J].Lipids Health Dis, 2020, 19(1):72.
[107]	HERNÁNDEZ-ALVAREZ M I, SEBASTIÁN D, VIVES S, et al.Deficient endoplasmic reticulum-mitochondrial phosphatidylserine transfer causes liver disease[J].Cell, 2019, 177(4):881-895.e17.
[108]	BURGOS-MORKÓN E, ABAD-JIMÉNEZ Z, DE MARAÑÓN A M, et al.Relationship between oxidative stress, ER stress, and inflammation in type 2 diabetes:the battle continues[J].J Clin Med, 2019, 8(9):1385.
[109]	WALTER P, RON D.The unfolded protein response:from stress pathway to homeostatic regulation[J].Science, 2011, 334(6059):1081-1086.
[110]	HENKEL A S.Unfolded protein response sensors in hepatic lipid metabolism and nonalcoholic fatty liver disease[J].Semin Liver Dis, 2018, 38(4):320-332.
[111]	SONG M J, MALHI H.The unfolded protein response and hepatic lipid metabolism in non alcoholic fatty liver disease[J].Pharmacol Ther, 2019, 203:107401.
[112]	GESEK M, SZAREK J, OTROCKA-DOMAGAŁA I, et al.Morphological pattern of the livers of different lines of broiler chickens during rearing[J].Vet Med, 2013, 58(1):16-24.
[113]	SCHUSTER S, CABRERA D, ARRESE M, et al.Triggering and resolution of inflammation in NASH[J].Nat Rev Gastroenterol Hepatol, 2018, 15(6):349-364.
[114]	PODSZUN M C, ALAWAD A S, LINGALA S, et al.Vitamin E treatment in NAFLD patients demonstrates that oxidative stress drives steatosis through upregulation of de-novo lipogenesis[J].Redox Biol, 2020, 37:101710.
[115]	ROSSATO M, DI VINCENZO A, PAGANO C, et al.The P2X7 receptor and NLRP3 axis in non-alcoholic fatty liver disease:A brief review[J].Cells, 2020, 9(4):1047.
[116]	SANDALL C F, MACDONALD J A.Effects of phosphorylation on the NLRP3 inflammasome[J].Arch Biochem Biophys, 2019, 670:43-57.
[117]	SONG N, LIU Z S, XUE W, et al.NLRP3 phosphorylation is an essential priming event for inflammasome activation[J].Mol Cell, 2017, 68(1):185-197.e6.
[118]	KELLEY N, JELTEMA D, DUAN Y H, et al.The NLRP3 inflammasome:an overview of mechanisms of activation and regulation[J].Int J Mol Sci, 2019, 20(13):3328.
[119]	SOKOLOVA M, YANG K, HANSEN S H, et al.NLRP3 inflammasome deficiency attenuates metabolic disturbances involving alterations in the gut microbial profile in mice exposed to high fat diet[J].Sci Rep, 2020, 10(1):21006.
[120]	WREE A, MCGEOUGH M D, PEÑA C A, et al.NLRP3 inflammasome activation is required for fibrosis development in NAFLD[J].J Mol Med (Berl), 2014, 92(10):1069-1082.
[121]	WREE A, EGUCHI A, MCGEOUGH M D, et al.NLRP3 inflammasome activation results in hepatocyte pyroptosis, liver inflammation, and fibrosis in mice[J].Hepatology, 2014, 59(3):898-910.
[122]	GAUL S, LESZCZYNSKA A, ALEGRE F, et al.Hepatocyte pyroptosis and release of inflammasome particles induce stellate cell activation and liver fibrosis[J].J Hepatol, 2021, 74(1):156-167.
[123]	SHEN Y, MALIK S A, AMIR M, et al.Decreased hepatocyte autophagy leads to synergistic IL-1β and TNF mouse liver injury and inflammation[J].Hepatology, 2020, 72(2):595-608.
[124]	ZHANG Z J, TIAN L, JIANG K.Propofol attenuates inflammatory response and apoptosis to protect D-galactosamine/lipopolysaccharide induced acute liver injury via regulating TLR4/NF-κB/NLRP3 pathway[J].Int Immunopharmacol, 2019, 77:105974.
[125]	LIAO J Z, YANG F, TANG Z X, et al.Inhibition of Caspase-1-dependent pyroptosis attenuates copper-induced apoptosis in chicken hepatocytes[J].Ecotoxicol Environ Saf, 2019, 174:110-119.
[126]	QU J R, WANG W, ZHANG Q J, et al.Inhibition of lipopolysaccharide-induced inflammation of chicken liver tissue by selenomethionine via TLR4-NF-κB-NLRP3 signaling pathway[J].Biol Trace Elem Res, 2020, 195(1):205-214.
[127]	FARZANEGI P, DANA A, EBRAHIMPOOR Z, et al.Mechanisms of beneficial effects of exercise training on non-alcoholic fatty liver disease (NAFLD):Roles of oxidative stress and inflammation[J].Eur J Sport Sci, 2019, 19(7):994-1003.
[128]	CRESPO J, CAYÓN A, FERNÁNDEZ-GIL P, et al.Gene expression of tumor necrosis factor alpha and TNF-receptors, p55 and p75, in nonalcoholic steatohepatitis patients[J].Hepatology, 2001, 34(6):1158-1163.
[129]	WANDRER F, LIEBIG S, MARHENKE S, et al.TNF-Receptor-1 inhibition reduces liver steatosis, hepatocellular injury and fibrosis in NAFLD mice[J].Cell Death Dis, 2020, 11(3):212.
[130]	KUNNUMAKKARA A, SHABNAM B, GIRISA S, et al.Inflammation, NF-κB, and chronic diseases:How are they linked?[J].Crit Rev Immunol, 2020, 40(1):1-39.
[131]	YAN H, GAO Y Q, ZHANG Y.Inhibition of JNK suppresses autophagy and attenuates insulin resistance in a rat model of nonalcoholic fatty liver disease[J].Mol Med Rep, 2017, 15(1):180-186.
[132]	FRIEDMAN S L, NEUSCHWANDER-TETRI B A, RINELLA M, et al.Mechanisms of NAFLD development and therapeutic strategies[J].Nat Med, 2018, 24(7):908-922.
[133]	GREGOR M F, HOTAMISLIGIL G S.Thematic review series:Adipocyte Biology.Adipocyte stress:the endoplasmic reticulum and metabolic disease[J].J Lipid Res, 2007, 48(9):1905-1914.
[134]	LORD G M, MATARESE G, HOWARD J K, et al.Leptin modulates the T-cell immune response and reverses starvation-induced immunosuppression[J].Nature, 1998, 394(6696):897-901.
[135]	KAKUMA T, LEE Y, HIGA M, et al.Leptin, troglitazone, and the expression of sterol regulatory element binding proteins in liver and pancreatic islets[J].Proc Natl Acad Sci U S A, 2000, 97(15):8536-8541.
[136]	CHOI S S, SYN W K, KARACA G F, et al.Leptin promotes the myofibroblastic phenotype in hepatic stellate cells by activating the hedgehog pathway[J].J Biol Chem, 2010, 285(47):36551-36560.
[137]	ALEFFI S, NAVARI N, DELOGU W, et al.Mammalian target of rapamycin mediates the angiogenic effects of leptin in human hepatic stellate cells[J].Am J Physiol Gastrointest Liver Physiol, 2011, 301(2):G210-G219.
[138]	TSOCHATZIS E, PAPATHEODORIDIS G V, HADZIYANNIS E, et al.Serum adipokine levels in chronic liver diseases:Association of resistin levels with fibrosis severity[J].Scand J Gastroenterol, 2008, 43(9):1128-1136.
[139]	MALIK S A, MARIÑO G, BENYOUNōS A, et al.Neuroendocrine regulation of autophagy by leptin[J].Cell Cycle, 2011, 10(17):2917-2923.
[140]	SEROUSSI E, CINNAMON Y, YOSEFI S, et al.Identification of the long-sought leptin in chicken and duck:expression pattern of the highly GC-rich avian leptin fits an autocrine/paracrine rather than endocrine function[J].Endocrinology, 2016, 157(2):737-751.
[141]	SEROUSSI E, PITEL F, LEROUX S, et al.Mapping of leptin and its syntenic genes to chicken chromosome 1p[J].BMC Genet, 2017, 18(1):77.
[142]	SEROUSSI E, KNYTL M, PITEL F, et al.Avian expression patterns and genomic mapping implicate leptin in digestion and TNF in immunity, suggesting that their interacting adipokine role has been acquired only in mammals[J].Int J Mol Sci, 2019, 20(18):4489.
[143]	TILG H, HOTAMISLIGIL G S.Nonalcoholic fatty liver disease:cytokine-adipokine interplay and regulation of insulin resistance[J].Gastroenterology, 2006, 131(3):934-945.
[144]	IWABU M, YAMAUCHI T, OKADA-IWABU M, et al.Adiponectin and AdipoR1 regulate PGC-1α and mitochondria by Ca2+ and AMPK/SIRT1[J].Nature, 2010, 464(7293):1313-1319.
[145]	ADACHI M, BRENNER D A.High molecular weight adiponectin inhibits proliferation of hepatic stellate cells via activation of adenosine monophosphate-activated protein kinase[J].Hepatology, 2008, 47(2):677-685.
[146]	XU A M, WANG Y, KESHAW H, et al.The fat-derived hormone adiponectin alleviates alcoholic and nonalcoholic fatty liver diseases in mice[J].J Clin Invest, 2003, 112(1):91-100.
[147]	OKADA-IWABU M, YAMAUCHI T, IWABU M, et al.A small-molecule AdipoR agonist for type 2 diabetes and short life in obesity[J].Nature, 2013, 503(7477):493-499.
[148]	ZHANG R, LIN Y, ZHI L, et al.Expression profiles and associations of adiponectin and adiponectin receptors with intramuscular fat in Tibetan chicken[J].Br Poult Sci, 2017, 58(2):151-157.
[149]	HENDRICKS III G L, HADLEY J A, KRZYSIK-WALKER S M, et al.Unique profile of chicken adiponectin, a predominantly heavy molecular weight multimer, and relationship to visceral adiposity[J].Endocrinology, 2009, 150(7):3092-3100.
[150]	WU W K K, ZHANG L, CHAN M T V.Autophagy, NAFLD and NAFLD-related HCC[M]//YU J.Obesity, Fatty Liver and Liver Cancer.Singapore:Springer, 2018:127-138.
[151]	GAO Y, ZHANG W, ZENG L Q, et al.Exercise and dietary intervention ameliorate high-fat diet-induced NAFLD and liver aging by inducing lipophagy[J].Redox Biol, 2020, 36:101635.
[152]	SINGH R, KAUSHIK S, WANG Y J, et al.Autophagy regulates lipid metabolism[J].Nature, 2009, 458(7242):1131-1135.
[153]	GREFHORST A, VAN DE PEPPEL I P, LARSEN L E, et al.The role of lipophagy in the development and treatment of non-alcoholic fatty liver disease[J].Front Endocrinol (Lausanne), 2021, 11:601627.
[154]	CAROTTI S, AQUILANO K, ZALFA F, et al.Lipophagy impairment is associated with disease progression in NAFLD[J].Front Physiol, 2020, 11:850.
[155]	骆佳, 徐金瑞, 李武, 等.BCG诱导RAW264.7细胞脂肪酸氧化对细胞自噬和促炎因子表达的调控作用[J].畜牧兽医学报, 2021, 52(9):2617-2625.LUO J, XU J R, LI W, et al.The effect of BCG-induced RAW264.7 cells fatty acid oxidation on autophagy and pro-inflammatory cytokines expression[J].Acta Veterinaria et Zootechnica Sinica, 2021, 52(9):2617-2625.(in Chinese)