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cm 0 0.938 0.765 0 k 0 0 m -5.58 3.718 l -5.58 8.182 l 0 8.182 l h f 1 0 0 1 -2.7901 -1.6484 cm 0.68401 0.09801 0.18401 0 k 0 0 m -2.568 0 -4.649 2.081 -4.649 4.648 c -4.649 7.216 -2.568 9.297 0 9.297 c 2.567 9.297 4.648 7.216 4.648 4.648 c 4.648 2.081 2.567 0 0 0 c 0 10.803 m -3.399 10.803 -6.154 8.047 -6.154 4.648 c -6.154 1.25 -3.399 -1.506 0 -1.506 c 3.399 -1.506 6.154 1.25 6.154 4.648 c 6.154 8.047 3.399 10.803 0 10.803 c f 1 0 0 1 3.4092 1.5019 cm 0 0.22 0.914 0 k 0 0 m -1.733 -1.889 -4.668 -2.014 -6.556 -0.28 c -7.98 1.027 -8.445 3.081 -7.721 4.874 c -9.01 5.694 l -10.406 2.595 -9.025 -1.049 -5.926 -2.444 c -3.426 -3.57 -0.482 -2.907 1.293 -0.817 c h f EMC Q BT /T1_2 1 Tf 0 Tw 8 0 0 8 42 487.9283 Tm [(T)85 (o cite )]TJ /T1_0 1 Tf [(Ampuero\036J)37.1 (,)37 ( Lucena\036)55 (A,)37 ( Hern\341ndez-)]TJ ET BT /Span <>BDC /T1_0 1 Tf 8 0 0 8 163.5432 487.9283 Tm ( )Tj EMC ET BT /T1_0 1 Tf 8 0 0 8 163.544 487.9283 Tm (Guerr)Tj 8 0 0 8 42 487.9283 Tm 17.213 0 Td [(a\036M,)37 ( )]TJ /T1_1 1 Tf -17.213 -1.141 Td (et\037al)Tj /T1_0 1 Tf -0.037 Tc 0.037 Tw (. )Tj /T1_1 1 Tf 0 Tc 0 Tw (Gut)Tj /T1_0 1 Tf ( 2022;)Tj /T1_2 1 Tf (71)Tj /T1_0 1 Tf (:2138\2262140.)Tj /T1_5 1 Tf 0 -1.641 TD (Received 21 July 2021)Tj /T1_0 1 Tf 0 -1.141 TD (Accepted 29 November 2021)Tj T* (Published Online First 7\036December\0362021)Tj /T1_1 1 Tf 0 -2.141 TD (Gut)Tj /T1_0 1 Tf ( 2022;)Tj /T1_2 1 Tf (71)Tj /T1_0 1 Tf [(:2138\2262140.)37 ( doi:10.1136/)]TJ 0 -1.141 TD (gutjnl-2021-325700)Tj /T1_2 1 Tf 0 -2.141 TD (ORCID iD)Tj /T1_0 1 Tf 0 -1.141 TD [(J)10 (avier\036)55 (Ampuero )]TJ 0 0 1 rg /GS1 gs (http://orcid.org/0000-0002-8332-2122)Tj 0 0 0 1 k /GS0 gs /T1_6 1 Tf 9.5 0 0 9.5 42 371.2583 Tm (REFERENCES)Tj ET BT /Span <>BDC /T1_0 1 Tf 7.5 0 0 7.5 42 362.1283 Tm ( )Tj EMC ET BT /T1_0 1 Tf 7.5 0 0 7.5 42 362.1283 Tm (1)Tj ET BT /Span <>BDC /T1_0 1 Tf 7.5 0 0 7.5 45.6 362.1283 Tm ( )Tj EMC ET BT /T1_0 1 Tf 7.5 0 0 7.5 51 362.1283 Tm (Mansoor E,)Tj 7.5 0 0 7.5 42 362.1283 Tm 5.292 0 Td [( )55 (Alikhan MM,)37.1 ( P)37 (erez JA,)37 ( )]TJ /T1_1 1 Tf (et\037al)Tj /T1_0 1 Tf [(.)37 ( Clinical )]TJ -4.092 -1.217 Td [(char)18 (acteristics)37 (,)37 ( hospitalisation and mortality r)18 (ates )]TJ 0 -1.217 TD [(of CO)18 (VID-)]TJ ET BT /Span <>BDC /T1_0 1 Tf 7.5 0 0 7.5 42 362.1283 Tm 4.869 -2.434 Td ( )Tj EMC ET BT /T1_0 1 Tf 7.5 0 0 7.5 78.5175 343.8733 Tm (19 among patients with coeliac disease )Tj -3.669 -1.217 Td (in the USA:)Tj 7.5 0 0 7.5 42 362.1283 Tm 5.2729 -3.651 Td [( a multicentre network study.)37 ( )]TJ 0 0 1 rg /GS1 gs /T1_1 1 Tf (Gut)Tj 0 0 0 1 k /GS0 gs /T1_0 1 Tf ( )Tj -4.0729 -1.217 Td (2022;71:1691\2262.)Tj ET BT /Span <>BDC /T1_0 1 Tf 7.5 0 0 7.5 42 316.4908 Tm ( )Tj EMC ET BT /T1_0 1 Tf 7.5 0 0 7.5 42 316.4908 Tm (2)Tj ET BT /Span <>BDC /T1_0 1 Tf 7.5 0 0 7.5 42 362.1283 Tm 0.48 -6.085 Td ( )Tj EMC ET BT /T1_0 1 Tf 7.5 0 0 7.5 51 316.4908 Tm (Iav)Tj 7.5 0 0 7.5 42 362.1283 Tm 2.238 -6.085 Td [(arone M,)37.1 ( D\222Ambrosio R,)37.1 ( Soria )55 (A,)37 ( )]TJ /T1_1 1 Tf (et\037al)Tj /T1_0 1 Tf [(.)37.1 ( High r)18 (ates )]TJ -1.038 -1.217 Td (of 30-)Tj ET BT /Span <>BDC /T1_0 1 Tf 7.5 0 0 7.5 42 362.1283 Tm 3.419 -7.302 Td ( )Tj EMC ET BT /T1_0 1 Tf 7.5 0 0 7.5 67.6425 307.3633 Tm (day mortality in patients with cirrhosis and )Tj -0.24001 Tw -2.219 -1.217 Td (CO)Tj 7.5 0 0 7.5 42 362.1283 Tm 2.313 -8.519 Td (VID-)Tj ET BT /Span <>BDC /T1_0 1 Tf 7.5 0 0 7.5 42 362.1283 Tm 3.906 -8.519 Td ( )Tj EMC ET BT /T1_0 1 Tf 7.5 0 0 7.5 42 362.1283 Tm 3.90599 -8.519 Td [(19.)37 ( )]TJ 0 0 1 rg /GS1 gs /T1_1 1 Tf 0 Tw 1.40301 0 Td (J Hepatol)Tj 0 0 0 1 k /GS0 gs /T1_0 1 Tf ( 2020;73:1063\22671.)Tj ET BT /Span <>BDC /T1_0 1 Tf 7.5 0 0 7.5 42 289.1083 Tm ( )Tj EMC ET BT /T1_0 1 Tf 7.5 0 0 7.5 42 289.1083 Tm (3)Tj ET BT /Span <>BDC /T1_0 1 Tf 7.5 0 0 7.5 42 362.1283 Tm 0.48 -9.736 Td ( )Tj EMC ET BT /T1_0 1 Tf 7.5 0 0 7.5 51 289.1083 Tm (Ampuero J)Tj 7.5 0 0 7.5 42 362.1283 Tm 5.035 -9.736 Td [(,)37 ( S\341nchez )55 (Y)128 (,)37 ( Garc\355a-)]TJ ET BT /Span <>BDC /T1_0 1 Tf 7.5 0 0 7.5 42 362.1283 Tm 12.069 -9.736 Td ( )Tj EMC ET BT /T1_0 1 Tf 7.5 0 0 7.5 132.5175 289.1083 Tm (Lozano MR,)Tj 7.5 0 0 7.5 42 362.1283 Tm 16.3459 -9.736 Td ( )Tj /T1_1 1 Tf (et\037al)Tj /T1_0 1 Tf [(.)37 ( Impact )]TJ -15.1459 -1.217 Td [(of liver injury on the severity of CO)18 (VID-)]TJ ET BT /Span <>BDC /T1_0 1 Tf 7.5 0 0 7.5 42 362.1283 Tm 15.334 -10.953 Td ( )Tj EMC ET BT /T1_0 1 Tf 7.5 0 0 7.5 157.005 279.9808 Tm (19:)Tj 7.5 0 0 7.5 42 362.1283 Tm 16.497 -10.953 Td ( a systematic )Tj -15.297 -1.217 Td (review with meta-)Tj ET BT /Span <>BDC /T1_0 1 Tf 7.5 0 0 7.5 42 362.1283 Tm 7.775 -12.17 Td ( )Tj EMC ET BT /T1_0 1 Tf 7.5 0 0 7.5 100.3125 270.8533 Tm (analysis)Tj 7.5 0 0 7.5 42 362.1283 Tm 10.571 -12.17 Td [(.)37 ( )]TJ 0 0 1 rg /GS1 gs /T1_1 1 Tf (Rev Esp Enferm Dig)Tj 0 0 0 1 k /GS0 gs /T1_0 1 Tf ( )Tj -9.371 -1.217 Td (2021;113:125\22635.)Tj ET BT /Span <>BDC /T1_0 1 Tf 7.5 0 0 7.5 42 252.5983 Tm ( )Tj EMC ET BT /T1_0 1 Tf 7.5 0 0 7.5 42 252.5983 Tm (4)Tj ET BT /Span <>BDC /T1_0 1 Tf 7.5 0 0 7.5 42 362.1283 Tm 0.48 -14.604 Td ( )Tj EMC ET BT /T1_0 1 Tf 7.5 0 0 7.5 51 252.5983 Tm (Belli LS)Tj 7.5 0 0 7.5 42 362.1283 Tm 3.756 -14.604 Td [(,)37 ( Duvoux C)37 (,)37 ( Cortesi P)55 (A,)37 ( )]TJ /T1_1 1 Tf (et\037al)Tj /T1_0 1 Tf [(.)37 ( CO)18 (VID-)]TJ ET BT /Span <>BDC /T1_0 1 Tf 7.5 0 0 7.5 42 362.1283 Tm 17.034 -14.604 Td ( )Tj EMC ET BT /T1_0 1 Tf 7.5 0 0 7.5 169.755 252.5983 Tm (19 in liver )Tj -15.834 -1.217 Td (tr)Tj 7.5 0 0 7.5 42 362.1283 Tm 1.738 -15.821 Td [(ansplant candidates:)37 ( pretr)18 (ansplant and post-)]TJ ET BT /Span <>BDC /T1_0 1 Tf 7.5 0 0 7.5 42 362.1283 Tm 17.958 -15.821 Td ( )Tj EMC ET BT /T1_0 1 Tf 7.5 0 0 7.5 176.685 243.4708 Tm (tr)Tj 7.5 0 0 7.5 42 362.1283 Tm 18.496 -15.821 Td (ansplant )Tj -17.296 -1.217 Td [(outcomes - an ELIT)45.1 (A/EL)91 (TR multicentre cohort study.)37 ( )]TJ 0 0 1 rg /GS1 gs /T1_1 1 Tf (Gut)Tj 0 0 0 1 k /GS0 gs /T1_0 1 Tf ( )Tj T* (2021;70:1914\22624.)Tj ET BT /Span <>BDC /T1_0 1 Tf 7.5 0 0 7.5 42 216.0883 Tm ( )Tj EMC ET BT /T1_0 1 Tf 7.5 0 0 7.5 42 216.0883 Tm (5)Tj ET BT /Span <>BDC /T1_0 1 Tf 7.5 0 0 7.5 42 362.1283 Tm 0.48 -19.472 Td ( )Tj EMC ET BT /T1_0 1 Tf 7.5 0 0 7.5 51 216.0883 Tm (Bollipo S)Tj 7.5 0 0 7.5 42 362.1283 Tm 4.3319 -19.472 Td [(,)36.9 ( Kapuria D)37 (,)37 ( Rabiee )55 (A,)37 ( )]TJ /T1_1 1 Tf (et\037al)Tj /T1_0 1 Tf [(.)37 ( One world,)36.9 ( one )]TJ -3.1319 -1.217 Td [(pandemic,)37 ( many guidelines:)37.1 ( management of liver )]TJ T* [(diseases during CO)18 (VID-)]TJ ET BT /Span <>BDC /T1_0 1 Tf 7.5 0 0 7.5 42 362.1283 Tm 9.739 -21.906 Td ( )Tj EMC ET BT /T1_0 1 Tf 7.5 0 0 7.5 115.0425 197.8333 Tm (19.)Tj 7.5 0 0 7.5 42 362.1283 Tm 10.902 -21.906 Td ( )Tj 0 0 1 rg /GS1 gs /T1_1 1 Tf (Gut)Tj 0 0 0 1 k /GS0 gs /T1_0 1 Tf ( 2020;69:1369\22672.)Tj ET BT /Span <>BDC /T1_0 1 Tf 7.5 0 0 7.5 42 188.7058 Tm ( )Tj EMC ET BT /T1_0 1 Tf 7.5 0 0 7.5 42 188.7058 Tm (6)Tj ET BT /Span <>BDC /T1_0 1 Tf 7.5 0 0 7.5 42 362.1283 Tm 0.48 -23.123 Td ( )Tj EMC ET BT /T1_0 1 Tf 7.5 0 0 7.5 51 188.7058 Tm (T)Tj 7.5 0 0 7.5 42 362.1283 Tm 1.552 -23.123 Td [(rivedi PJ)37 (,)37 ( Hirsch\037eld GM.)37 ( Recent adv)18 (ances in clinical )]TJ -0.352 -1.217 Td [(pr)18 (actice:)37 ( epidemiology of autoimmune liver diseases)37 (.)37 ( )]TJ 0 0 1 rg /GS1 gs /T1_1 1 Tf T* (Gut)Tj 0 0 0 1 k /GS0 gs /T1_0 1 Tf ( 2021;70:1989\2262003.)Tj /T1_3 1 Tf 13.5 0 0 13.5 42 144.8983 Tm (Insuf\037cient evidence for NTCP )Tj 0 -1.111 TD (activity in stellate\036cells)Tj /TT0 1 Tf 0.021 Tc -0.06 Tw 9 0 0 9 42 101.7683 Tm [(W)118.6 (e read with interest the study of Salhab)21.1 ( )]TJ 0.493 Tw 0 -1.237 TD [(postulating the sodium+/taurocholate)21.1 ( )]TJ 0.27499 Tw T* [(cotransporting )0.5 (polypeptide \(NTCP\) as)20.9 ( )]TJ 0.40601 Tw T* [(novel )0.5 (therapeutic target )0.5 (against liver)20.9 ( )]TJ -0.021 Tw T* (fibrosis.)Tj 0 0 1 rg /GS1 gs 0 Tc 0 Tw 5.967 0 0 5.967 74.1199 61.2983 Tm (1)Tj 0 0 0 1 k /GS0 gs 0.021 Tc 0.662 Tw 9 0 0 9 77.5638 57.2483 Tm ( The authors report func)Tj 0 Tc 0 Tw (-)Tj 0.021 Tc 0.011 Tw -3.952 -1.237 Td [(tional expression of the bile acid uptake)21.1 ( )]TJ 0.37199 Tw 19.399 55.69 Td [(transporter NTCP in primary human)20.8 ( )]TJ 0.588 Tw 0 -1.222 TD [(hepatic )0.7 (stellate )0.8 (and )0.7 (LX2 )0.7 (cells )0.7 (and)20.8 ( )]TJ 0.172 Tw T* [(suggest a role for NTCP)72.6 (-)]TJ ET BT /Span <>BDC /TT0 1 Tf 9 0 0 9 77.5638 57.2483 Tm 27.27029 52.009 Td ( )Tj EMC ET BT /TT0 1 Tf 9 0 0 9 323.0028 525.3293 Tm (mediated bile)Tj 9 0 0 9 77.5638 57.2483 Tm 33.45785 52.009 Td ( )Tj -0.006 Tw -18.01085 -1.222 Td [(salt uptake )0.5 (and consequent )0.5 (activation )0.5 (of)21 ( )]TJ 0.037 Tw T* [(stellate cells in the pathogenesis of liver)20.8 ( )]TJ -0.021 Tw T* (fibrosis.)Tj 0.556 Tw 1 -1.222 Td [(The authors used a commercially)20.8 ( )]TJ -0.00301 Tw -1 -1.222 Td [(available antibody against human NTCP)20.8 ( )]TJ 0.52901 Tw T* [(for immunofluorescent stainings and)20.9 ( )]TJ 0.5 Tw T* [(W)118.6 (estern blots, fluorescence activated)20.8 ( )]TJ 0.319 Tw T* [(cell )0.5 (sorting )0.5 (\(F)63.7 (A)17.6 (C)-28 (S\) )0.5 (analysis )0.5 (and )0.5 (as )0.5 (a)21.2 ( )]TJ 0.06 Tw T* [(neutralising )0.5 (antibody )0.5 (in )0.5 (bile )0.5 (salt )0.5 (uptake)21.1 ( )]TJ 0.243 Tw T* [(experiments. )0.5 (R)22.1 (emarkably)114.5 (, )0.5 (despite )0.5 (high)20.8 ( )]TJ 0.12801 Tw T* [(immunopositive signals, no cell surface)21.1 ( )]TJ 0.14999 Tw T* (signal was observed in the immunoflu)Tj 0 Tc 0 Tw (-)Tj 0.021 Tc 0.168 Tw T* [(orescent stainings. Using this antibody)114.6 (,)21.1 ( )]TJ 0.314 Tw T* [(the authors show complete inhibition)20.8 ( )]TJ 0.26401 Tw T* [(of NTCP)72.6 (-)]TJ ET BT /Span <>BDC /TT0 1 Tf 9 0 0 9 77.5638 57.2483 Tm 20.06738 33.679 Td ( )Tj EMC ET BT /TT0 1 Tf 9 0 0 9 258.1668 360.3593 Tm (mediated bile salt uptake in)Tj 9 0 0 9 77.5638 57.2483 Tm 33.45912 33.679 Td ( )Tj 0.004 Tw -18.01212 -1.222 Td [(LX2 )0.7 (cells, )0.7 (whereas )0.7 (the )0.7 (epitope )0.7 (to )0.7 (which)20.8 ( )]TJ 0.07401 Tw T* (the antibody was raised is mostly intra)Tj 0 Tc 0 Tw (-)Tj 0.021 Tc 0.16701 Tw T* [(cellular)54.5 (. )0.8 (In )0.7 (addition, )0.7 (the )0.7 (NTCP )0.7 (migra)]TJ 0 Tc 0 Tw (-)Tj 0.021 Tc 0.414 Tw T* [(tion pattern shown on W)118.6 (estern blot)20.9 ( )]TJ 0.17 Tw T* [(deviates from the characteristic diffuse)21.1 ( )]TJ 0.16 Tw 19.399 26.889 Td (NTCP migration pattern seen in hepa)Tj 0 Tc 0 Tw (-)Tj 0.021 Tc 0.244 Tw T* [(tocellular lysates as well as in NTCP)72.6 (-)]TJ ET BT /Span <>BDC /TT0 1 Tf 9 0 0 9 553.2678 536.3723 Tm ( )Tj EMC ET BT /TT0 1 Tf 0.311 Tw 9 0 0 9 391.1778 525.3743 Tm (overexpressing cell lines.)Tj 0 0 1 rg /GS1 gs 0 Tc 0 Tw 5.967 0 0 5.967 497.3397 529.379 Tm (2)Tj 0 0 0 1 k /GS0 gs 0.021 Tc 0.311 Tw 9 0 0 9 500.7836 525.329 Tm [( NTCP is a)21.2 ( )]TJ -0.069 Tw -12.178 -1.222 Td [(heavily glycosylated protein and we have)21.1 ( )]TJ 0.01601 Tw T* [(previously shown that this glycosylation)20.9 ( )]TJ -0.05299 Tw T* (is essential for its plasma membrane traf)Tj 0 Tc 0 Tw 17.677 0 Td (-)Tj 0.021 Tc -17.677 -1.222 Td [(ficking and activity)114.6 (.)]TJ 0 0 1 rg /GS1 gs 0 Tc 5.967 0 0 5.967 470.0443 485.379 Tm (2)Tj 0 0 0 1 k /GS0 gs 0.364 Tw 9 0 0 9 400.1837 470.329 Tm [(A highly interesting though )-0.8 (puzzling )]TJ 0.459 Tw -1 -1.222 Td [(observation )-0.6 (is the beneficial )0.9 (effect of )]TJ 0.091 Tw T* [(NTCP neutralisation )0.5 (on fibrosis develop)]TJ 0 Tw (-)Tj 0.123 Tw T* [(ment in a )0.5 (CCL)]TJ 0 Tw 5.247 0 0 5.247 451.6202 434.332 Tm (4)Tj 0.123 Tw 9 0 0 9 454.5383 437.329 Tm ( mouse model. The anti)Tj 0 Tw (-)Tj 0.02299 Tw -7.039 -1.222 Td (body used to neutralise mouse NTCP was )Tj 0.23199 Tw T* [(raised in rabbits and targets a )0.6 (synthetic )]TJ 0.034 Tw T* [(peptide corresponding )-1.4 (to the intracellular )]TJ -0.00999 Tw T* [(C terminal )0.6 (region of mouse NTCP)202.4 (. There)]TJ 0 Tw (-)Tj 0.015 Tw T* [(fore, it is unclear)0.5 ( how this antibody could )]TJ -0.033 Tw T* [(operate as a block)0.5 (ing antibody)114.5 (. The effects )]TJ 0.15199 Tw T* (observed in the mouse model of fibrosis )Tj 0.11099 Tw T* [(may be )0.7 (related )0.6 (to an )0.5 (acute )0.9 (inflammatory )]TJ 0.02 Tw T* [(response elicited )1.3 (by )0.6 (the )0.5 (use )0.7 (of )0.5 (rabbit )0.9 (anti)]TJ 0 Tw (-)Tj 0.106 Tw T* (bodies in mice. No antibody control was )Tj 0.218 Tw T* [(used )0.6 (in )0.7 (this experiment. )0.6 (W)118.6 (e )0.8 (and )0.6 (others )]TJ 0.248 Tw T* [(have )0.6 (previously demonstrated that )0.8 (both )]TJ ET q 1 0 0 1 36.969 40.912 cm 0 g 0 G 1 w /GS2 gs 0 Tw /Fm1 Do Q q 1 0 0 1 214.23 41.724 cm 0 g 0 G 1 w /GS2 gs 0 Tw /Fm2 Do Q BT 0 g /GS2 gs /T1_7 1 Tf 0 Tw 0 -9 9 0 578 291.20479 Tm ( on September 23, 2022 by guest. Protected by copyright.)Tj 0 0 1 rg /GS2 gs -8.22598 0 Td (http://gut.bmj.com/)Tj 0 g /GS2 gs -40.74293 0 Td (Gut: first published as 10.1136/gutjnl-2021-325700 on 7 December 2021. 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