TLR4 Knockout Attenuates BDL-induced Liver Cholestatic Injury through Amino Acid and Choline Metabolic Pathways

Abstract

The exact mechanism by which knockout of Toll-like receptor 4 (TLR4) attenuates the liver injury remains unclear. The present study aimed to examine the role of TLR4 in the pathogenesis of bile duct ligation (BDL)-induced liver cholestatic injury and the underlying mechanism. Wild type (WT) mice and TLR4 knockout (TLR4-KO) mice were used for the establishment of the BDL model. Metabolomics were applied to analyze the changes of small molecular metabolites in the serum and liver of the two groups. The serum biochemical indexes and the HE staining results of liver tissue showed that liver damage was significantly reduced in TLR4-KO mice after BDL when compared with that in WT mice. The metabolite analysis results showed that TLR4 KO could maintain the metabolisms of amino acids- and choline-related metabolites. After BDL, the amino acids- and choline-related metabolites, especially choline and 3-hydroxybutyrate, were significantly increased in WT mice (both in serum and liver), but these metabolites in the liver of TLR4-KO mice after BLD were not significant different from those before BLD. In conclusion, TLR4 KO could attenuate BDL-induced liver cholestatic injury through regulating amino acid and choline metabolic pathways.

Keywords

Toll-like receptor 4 / biliary obstruction / metabolomics / liver / bile duct ligation

References

[1] OyaS, YokoyamaY, KokuryoT, et al.. Inhibition of Toll-like receptor 4 suppresses liver injury induced by biliary obstruction and subsequent intraportal lipopolysaccharide injection. Am J Physiol Gastrointest Liver Physiol, 2014, 306(3): G244-G252

[2] UenoK, AjikiT, WatanabeH, et al.. Changes in extrathymic T cells in the liver and intestinal intraepithelium in mice with obstructive jaundice. World J Surg, 2004, 28(3): 277-282

[3] AbrahamS, HermeszE, SzaboA, et al.. Effects of Kupffer cell blockade on the hepatic expression of metallothionein and heme oxygenase genes in endotoxemic rats with obstructive jaundice. Life Sci, 2012, 90(3–4): 140-146

[4] BrandoniA, Di GiustoG, FrancaR, et al.. Expression of kidney and liver bilitranslocase in response to acute biliary obstruction. Nephron Physiol, 2010, 114(4): p35-40

[5] PenkovN. Pathogenetic mechanisms in biliary obstruction (literature review). Khirurgiia (Sofiia), 2003, 59(1–2): 39-45

[6] SepehriZ, KianiZ, KohanF, et al.. Toll like receptor 4 and hepatocellular carcinoma; A systematic review. Life Sci, 2017, 179: 80-87

[7] Zare-BidakiM, Tsukiyama-KoharaK, ArababadiMK. Toll-like receptor 4 and hepatitis B infection: molecular mechanisms and pathogenesis. Viral Immunol, 2014, 27(7): 321-326

[8] GuoJ, FriedmanSL. Toll-like receptor 4 signaling in liver injury and hepatic fibrogenesis. Fibrogenesis Tissue Repair, 2010, 3: 21

[9] PradereJP, TroegerJS, DapitoDH, et al.. Toll-like receptor 4 and hepatic fibrogenesis. Semin Liver Dis, 2010, 30(3): 232-244

[10] TangSF, ZhaoLJ. Action and mechanism of LPS/TLR4 signaling pathway in hepatolithiasis: recent progress. Chin J Gener Surg (Chinese), 2017, 26(2): 235-240

[11] NabihES, El-KharashiOA. Targeting HMGB1/TLR4 axis and miR-21 by rosuvastatin: role in alleviating cholestatic liver injury in a rat model of bile duct ligation. Naunyn Schmiedebergs Arch Pharmacol, 2019, 392(1): 37-43

[12] ZhaoDY, HanLS, HeZJ, et al.. Identification of the Plasma Metabolomics as Early Diagnostic Markers between Biliary Atresia and Neonatal Hepatitis Syndrome. PLoS One, 2014, 9(1): e85694

[13] ZhouK, WangJ, XieG, et al.. Distinct Plasma Bile Acid Profiles of Biliary Atresia and Neonatal Hepatitis Syndrome. J Proteome Res, 2015, 14(11): 4844-4850

[14] ZhouK, XieG, WenJ, et al.. Histamine is correlated with liver fibrosis in biliary atresia. Dig Liver Dis, 2016, 48(8): 921-926

[15] LeeP, ParkHJ, ChoN, et al.. 3,5-Diethoxy-3′-Hydroxyresveratrol (DEHR) Ameliorates Liver Fibrosis via Caveolin-1 Activation in Hepatic Stellate Cells and in a Mouse Model of Bile Duct Ligation Injury. Molecules, 2018, 23(11): 2833

[16] XieB, LiuA, ZhanX, et al.. Alteration of gut bacteria and metabolomes after glucaro-1,4-lactone treatment contributes to the prevention of hypercholesterolemia. J Agric Food Chem, 2014, 62(30): 7444-7451

[17] MickiewiczB, VogelHJ, WongHR, et al.. Metabolomics as a novel approach for early diagnosis of pediatric septic shock and its mortality. Am J Respir Crit Care Med, 2013, 187(9): 967-976

[18] AmathieuR, TribaMN, NahonP, et al.. Serum ¹H-NMR metabolomic fingerprints of acute-on-chronic liver failure in intensive care unit patients with alcoholic cirrhosis. PLoS One, 2014, 9(2): e89230

[19] YuMJ, XiangTX, WuXP, et al.. Diagnosis of acute pediatric appendicitis from children with inflammatory diseases by combination of metabolic markers and inflammatory response variables. Clin Chem Lab Med, 2018, 56(6): 1001-1010

[20] YinPY, WanDF, ZhaoCX, et al.. A metabonomic study of hepatitis B-induced liver cirrhosis and hepatocellular carcinoma by using RP-LC and HILIC coupled with mass spectrometry. Mol Biosyst, 2009, 5(8): 868-876

[21] ZhengP, GaoHC, LiQ, et al.. Plasma Metabonomics as a Novel Diagnostic Approach for Major Depressive Disorder. J Prot Res, 2012, 11(3): 1741-1748

[22] MamtiminB, XiaG, MijitM, et al.. Metabolic differentiation and classification of abnormal Savda Munziq’s pharmacodynamic role on rat models with different diseases by nuclear magnetic resonance-based metabonomics. Pharmacogn Mag, 2015, 11(44): 698-706

[23] LiM, YinL, LiuP, et al.. LPS increases the liver injury viaTLR4 dependent manner in mice with acute obstructive jaundice. J Hepatobiliary Surg, 2010, 18(3): 224-227

[24] Zhu J, Lu T, Chen F, et al. Choline Protects Against Intestinal Failure-Associated Liver Disease in Parenteral Nutrition-Fed Immature Rats. JPEN J Parenter Enteral Nutr, 2016:148607116677048

[25] YamamotoH, KannoK, IkutaT, et al.. Enhancing hepatic fibrosis in spontaneously hypertensive rats fed a choline-deficient diet: a follow-up report on long-term effects of oxidative stress in non-alcoholic fatty liver disease. J Hepatobiliary Pancreat Sci, 2016, 23(5): 260-269

[26] SherriffJL, O’SullivanTA, ProperziC, et al.. Choline, Its Potential Role in Nonalcoholic Fatty Liver Disease, and the Case for Human and Bacterial Genes. Adv Nutr, 2016, 7(1): 5-13

[27] MikamiD, KobayashiM, UwadaJ, et al.. β-Hydroxy-butyrate, a ketone body, reduces the cytotoxic effect of cisplatin via activation of HDAC5 in human renal cortical epithelial cells. Life Sci, 2019, 222: 125-132

[28] DuX, LiuG, LoorJJ, et al.. Impaired hepatic autophagic activity in dairy cows with severe fatty liver is associated with inflammation and reduced liver function. J Dairy Sci, 2018, 101(12): 11 175-11 185

[29] ChangZ, WangH, LiB, et al.. Metabolic Characterization of Peripheral Host Responses to Drainage-Resistant Klebsiella pneumoniae Liver Abscesses by Serum 1H-NMR Spectroscopy. Front Cell Infect Microbiol, 2018, 8: 174

[30] LamontagneRJ, CascianoJC, BouchardMJ. A broad investigation of the HBV-mediated changes to primary hepatocyte physiology reveals HBV significantly alters metabolic pathways. Metabolism, 2018, 83: 50-59

[31] YangW, ZhouG, ZouS, et al.. Metabonomics of d-glucaro-1,4-lactone in preventing diethylnitrosamine-induced liver cancer in rats. Pharm Biol, 2018, 56(1): 643-648