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f
Q
q
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0.573 -1.079 0.557 -1.202 0.559 -1.323 c
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0.013 0 l
0 0 l
f
Q
q
1 0 0 1 54.833 746.4838 cm
0 0 m
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0 0 l
f
Q
q
1 0 0 1 57.3232 747.7289 cm
0 0 m
0.001 0.116 -0.014 0.231 -0.044 0.342 c
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h
-1.9 1.238 m
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-1.315 1.033 -1.202 1.141 -1.064 1.205 c
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0.028 1.129 0.151 1.031 0.249 0.911 c
0.348 0.787 0.42 0.644 0.464 0.491 c
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-1.9 1.238 l
f
Q
q
1 0 0 1 58.7451 747.6918 cm
0 0 m
0 -0.105 0.015 -0.209 0.042 -0.311 c
0.065 -0.408 0.107 -0.501 0.164 -0.584 c
0.22 -0.663 0.292 -0.729 0.376 -0.774 c
0.569 -0.873 0.799 -0.873 0.993 -0.774 c
1.079 -0.726 1.152 -0.656 1.208 -0.573 c
1.266 -0.488 1.307 -0.393 1.331 -0.293 c
1.357 -0.187 1.367 -0.079 1.365 0.03 c
1.38 0.259 1.315 0.485 1.182 0.672 c
1.061 0.822 0.876 0.905 0.684 0.898 c
0.569 0.901 0.457 0.874 0.359 0.819 c
0.272 0.768 0.198 0.698 0.144 0.614 c
0.087 0.526 0.047 0.429 0.024 0.327 c
0.005 0.219 -0.004 0.11 0 0 c
1.907 -1.208 m
1.39 -1.208 l
1.39 -0.866 l
1.322 -1.004 1.208 -1.112 1.068 -1.174 c
0.93 -1.235 0.778 -1.267 0.625 -1.266 c
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-0.103 1.136 0.015 1.215 0.144 1.266 c
0.27 1.315 0.404 1.341 0.54 1.341 c
0.618 1.341 0.697 1.334 0.774 1.32 c
0.854 1.306 0.93 1.283 1.004 1.251 c
1.076 1.22 1.144 1.179 1.205 1.129 c
1.271 1.075 1.324 1.009 1.365 0.935 c
1.365 2.197 l
1.911 2.197 l
1.911 -1.215 l
1.907 -1.208 l
f
Q
q
1 0 0 1 62.7646 747.7152 cm
0 0 m
-0.093 -0.057 -0.198 -0.091 -0.307 -0.099 c
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h
0.545 -0.682 m
0.542 -0.731 0.552 -0.781 0.573 -0.825 c
0.597 -0.856 0.636 -0.874 0.676 -0.87 c
0.809 -0.87 l
0.809 -1.249 l
0.733 -1.268 l
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0.468 -1.289 l
0.371 -1.292 0.275 -1.268 0.191 -1.221 c
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0.021 0.408 0.042 0.473 0.037 0.539 c
0.04 0.601 0.022 0.66 -0.014 0.71 c
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-0.717 1.275 -0.582 1.287 -0.447 1.286 c
-0.332 1.286 -0.218 1.273 -0.106 1.249 c
0.006 1.227 0.113 1.185 0.212 1.126 c
0.305 1.071 0.383 0.995 0.44 0.904 c
0.502 0.802 0.531 0.683 0.525 0.563 c
0.525 -0.706 l
0.545 -0.682 l
f
Q
q
1 0 0 1 63.6523 748.9672 cm
0 0 m
0.408 0 l
0.408 0.727 l
0.954 0.727 l
0.954 0 l
1.445 0 l
1.445 -0.406 l
0.954 -0.406 l
0.954 -1.74 l
0.952 -1.788 0.952 -1.837 0.954 -1.886 c
0.958 -1.924 0.97 -1.96 0.989 -1.992 c
1.008 -2.023 1.035 -2.045 1.067 -2.058 c
1.113 -2.072 1.162 -2.079 1.211 -2.077 c
1.326 -2.077 l
1.365 -2.081 1.403 -2.081 1.442 -2.077 c
1.442 -2.497 l
1.266 -2.518 l
1.088 -2.518 l
0.973 -2.519 0.858 -2.506 0.746 -2.477 c
0.669 -2.455 0.599 -2.414 0.541 -2.357 c
0.491 -2.302 0.457 -2.232 0.443 -2.159 c
0.424 -2.07 0.413 -1.979 0.412 -1.886 c
0.412 -0.42 l
0.003 -0.42 l
0.003 0 l
0 0 l
f
Q
q
1 0 0 1 67.1797 747.9203 cm
0 0 m
-0.007 0.085 -0.024 0.169 -0.055 0.249 c
-0.083 0.325 -0.124 0.396 -0.178 0.457 c
-0.232 0.517 -0.297 0.565 -0.369 0.601 c
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-1.243 0.183 -1.264 0.104 -1.269 0.023 c
0 0.023 l
h
-1.269 -0.341 m
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0.515 -0.665 l
0.463 -0.916 0.319 -1.14 0.112 -1.289 c
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0.048 0.891 0.18 0.779 0.282 0.645 c
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0.552 0.009 0.564 -0.172 0.542 -0.352 c
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-1.269 -0.341 l
f
Q
q
1 0 0 1 68.5576 747.2621 cm
0 0 m
-0.001 -0.137 0.067 -0.265 0.181 -0.341 c
0.295 -0.408 0.427 -0.441 0.56 -0.436 c
0.617 -0.44 0.675 -0.44 0.733 -0.436 c
0.798 -0.413 0.858 -0.382 0.914 -0.341 c
0.968 -0.321 1.017 -0.287 1.054 -0.242 c
1.093 -0.194 1.111 -0.133 1.105 -0.071 c
1.104 -0.008 1.076 0.055 1.03 0.099 c
0.977 0.146 0.913 0.182 0.847 0.204 c
0.763 0.233 0.677 0.256 0.59 0.273 c
0.3 0.334 l
0.2 0.356 0.104 0.384 0.007 0.415 c
-0.088 0.44 -0.178 0.481 -0.26 0.531 c
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-0.487 0.838 -0.512 0.945 -0.509 1.054 c
-0.514 1.176 -0.479 1.295 -0.41 1.395 c
-0.344 1.485 -0.259 1.561 -0.16 1.613 c
-0.054 1.671 0.061 1.71 0.181 1.729 c
0.293 1.751 0.407 1.762 0.523 1.764 c
0.645 1.764 0.768 1.75 0.887 1.723 c
0.997 1.697 1.104 1.653 1.201 1.593 c
1.298 1.536 1.382 1.458 1.446 1.364 c
1.51 1.261 1.549 1.144 1.561 1.023 c
1.003 1.023 l
0.99 1.135 0.922 1.233 0.822 1.285 c
0.721 1.333 0.609 1.357 0.498 1.354 c
0.361 1.354 l
0.312 1.349 0.263 1.338 0.215 1.32 c
0.171 1.304 0.132 1.278 0.099 1.245 c
0.066 1.21 0.05 1.163 0.051 1.115 c
0.049 1.053 0.073 0.993 0.119 0.951 c
0.172 0.906 0.234 0.871 0.3 0.849 c
0.384 0.82 0.469 0.798 0.556 0.781 c
0.853 0.682 l
0.95 0.659 1.047 0.631 1.143 0.601 c
1.234 0.57 1.32 0.526 1.399 0.47 c
1.474 0.416 1.535 0.347 1.579 0.266 c
1.628 0.171 1.651 0.065 1.648 -0.041 c
1.651 -0.173 1.616 -0.301 1.549 -0.413 c
1.483 -0.515 1.394 -0.6 1.29 -0.662 c
1.184 -0.726 1.069 -0.772 0.948 -0.803 c
0.822 -0.831 0.692 -0.846 0.562 -0.847 c
0.417 -0.849 0.271 -0.831 0.129 -0.796 c
0.007 -0.764 -0.108 -0.709 -0.212 -0.635 c
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-0.503 -0.256 -0.539 -0.13 -0.546 0 c
0 0 l
f
Q
0.146 0.939 1 0.048 scn
q
1 0 0 1 57.8418 760.4135 cm
0 0 m
7.267 4.845 l
7.267 10.654 l
0 10.654 l
h
f
Q
0 0.891 0.683 0 scn
q
1 0 0 1 65.1084 760.4135 cm
0 0 m
-7.267 4.845 l
-7.267 10.654 l
0 10.654 l
h
f
Q
0.688 0.074 0.203 0 scn
q
1 0 0 1 61.4746 758.2642 cm
0 0 m
-3.344 0 -6.055 2.711 -6.055 6.055 c
-6.055 9.4 -3.344 12.111 0 12.111 c
3.345 12.111 6.056 9.4 6.056 6.055 c
6.056 2.711 3.345 0 0 0 c
0 14.073 m
-4.428 14.073 -8.017 10.483 -8.017 6.055 c
-8.017 1.628 -4.428 -1.961 0 -1.961 c
4.428 -1.961 8.018 1.628 8.018 6.055 c
8.018 10.483 4.428 14.073 0 14.073 c
f
Q
0 0.241 0.862 0 scn
q
1 0 0 1 65.9102 760.2255 cm
0 0 m
-2.277 -2.443 -6.106 -2.577 -8.55 -0.299 c
-10.368 1.396 -10.963 4.033 -10.051 6.346 c
-11.73 7.407 l
-13.586 3.392 -11.836 -1.369 -7.82 -3.226 c
-4.525 -4.751 -0.614 -3.867 1.706 -1.071 c
0 0 l
f
Q
EMC
Q
BT
/T1_0 1 Tf
-0.02 Tc
0.027 Tw
9.5 0 0 9.5 309 474.4381 Tm
[ (levels wer) 9 (e con\037r) -36 (med in murine N) -15 (A) -15 (S) -15 (H) -15 ( ) -14.9 (l) -15 (i) -15 (v) -15 (e) -15 (r) -15 ( ) -14.9 (s) -15 (a) -15 (m) -15 (p) -15 (l) -15 (e) -15 (s) -15 (\056) ] TJ
ET
q
525.22 474.438 9.144 7.128 re
W
n
q
/GS1 gs
9.144 0 0 7.128 525.22064 474.4381 cm
/Im0 Do
Q
Q
BT
/T1_0 1 Tf
-0.005 Tc
9.5 0 0 9.5 534.3171 474.4381 Tm
[ ( Our) -5 ( ) ] TJ
0.125 Tw
-23.718 -1.105 Td
[ (r) 9 (esults suggest incr) 9 (eased bile acid synthesis in NASH s) 14.9 (a) 15.1 (m) ] TJ
0 Tc
0 Tw
25.549 0 Td
(\055) Tj
-0.02 Tc
0.05 Tw
-25.549 -1.105 Td
(ples\054 as judged by the enhanced level of 7) Tj
/T1_2 1 Tf
0 Tc
0 Tw
(\037) Tj
/T1_0 1 Tf
-0.02 Tc
0.02 Tw
18.29 0 Td
[ (\055hydr) 15 (oxycholest\0554) -14.9 (\055) ] TJ
-0.005 Tc
0.161 Tw
-18.29 -1.105 Td
[ (en\0553\055one and impair) 9 (ed 24) ] TJ
/T1_3 1 Tf
0 Tc
0 Tw
(S) Tj
/T1_0 1 Tf
-0.005 Tc
0.161 Tw
11.903 0 Td
[ (\055hydr) 15 (oxycholester) 15 (ol metabolism) -5 ( ) ] TJ
0.156 Tw
-11.903 -1.105 Td
[ (as characteristic biochemical changes in livers af) 34 (fected by) -5 ( ) ] TJ
-0.027 Tc
0.027 Tw
0 -1.105 TD
(NASH\056) Tj
/T1_1 1 Tf
-0.045 Tw
[ (\227Raselli\054 T) 103.1 (\056\054 ) 0.5 (T) 103 (\056 ) 0.5 (Hearn\054 A\056 W) -1.9 (yss\054 ) 0.5 (K\056 ) 0.5 (Atrott\054 ) 0.5 (A\056 ) 0.5 (Peter) 84 (\054 ) 0.5 (I\056 ) 0.5 (Frey\055) ] TJ
0.027 Tw
T*
[ (W) 38 (agner) 84 (\054 M\056 R\056 Spalinger) 84 (\054 E\056 M\056 Maggio\054 A\056 W) 55 (\056 Sailer) 84 (\054 J\056 Schmitt\054) -27 ( ) ] TJ
0.053 Tw
0 -1.105 TD
[ (P) 118 (\056 Schreiner) 84.1 (\054 A\056 Moncsek\054 J\056 Mertens\054 M\056 Scharl\054 W) 55 (\056 J\056 Grif\037ths\054) -27 ( ) ] TJ
-0.02 Tc
0.006 Tw
0 -1.105 TD
[ (M\056 Bueter) 84 (\054 A\056 Geier) 84 (\054 G\056 Rogler) 84 (\054 Y) 90 (\056 W) 38 (ang\054 and B\056 Misselwitz\056 ) ] TJ
/T1_0 1 Tf
0 Tc
0 Tw
(Ele) Tj
(\055) Tj
-0.01 Tc
-0.002 Tw
T*
[ (vated oxyster) 15 (ol levels in human and mouse livers r) 9 (e\036ect non) ] TJ
0 Tc
0 Tw
(\055) Tj
-0.01 Tc
T*
(alcoholic steatohepatitis\056) Tj
/T1_1 1 Tf
0 Tc
( ) Tj
/T1_3 1 Tf
-0.01 Tc
0.01 Tw
10.75 0 Td
(J\056) Tj
/T1_4 1 Tf
0 Tc
0 Tw
( ) Tj
/T1_3 1 Tf
-0.01 Tc
0.01 Tw
0.85 0 Td
(Lipid) Tj
/T1_4 1 Tf
0 Tc
0 Tw
( ) Tj
/T1_3 1 Tf
-0.01 Tc
0.01 Tw
2.42 0 Td
(Res\056) Tj
/T1_1 1 Tf
0 Tc
0 Tw
( ) Tj
/T1_0 1 Tf
-0.01 Tc
0.01 Tw
1.87 0 Td
(2019\056) Tj
/T1_1 1 Tf
0 Tw
( 60\072 ) Tj
/T1_0 1 Tf
0.01 Tw
(1270\2261283\056) Tj
-0.005 Tc
0.139 Tw
8 0 0 8 309 345.4381 Tm
[ (Supplementar) -56 (y ) 0.5 (key ) 0.6 (wor) 10 (ds) ] TJ
/T1_1 1 Tf
/Span <<
/ActualText (\376\377 \003)
>> BDC
( ) Tj
EMC
12.363 0 Td
[ (nonalcoholic ) 0.5 (fatty ) 0.6 (liver ) 0.6 (disease) ] TJ
/Span <<
/ActualText (\376\377\000\240)
>> BDC
( ) Tj
EMC
13.949 0 Td
[ <7f20> 0.5 (Epstein\055) ] TJ
-0.036 Tw
-26.312 -1.125 Td
(Barr virus\055induced gene 2) Tj
/Span <<
/ActualText (\376\377\000\240)
>> BDC
( ) Tj
EMC
<7f2063686f6c65737465726f6c20323520687964726f78796c617365> Tj
/Span <<
/ActualText (\376\377\000\240)
>> BDC
( ) Tj
EMC
<7f2032352d687964726f787963686f> Tj
0 Tc
0 Tw
(\055) Tj
-0.005 Tc
0 -1.125 TD
(lesterol 7) Tj
/T1_5 1 Tf
0 Tc
(\037) Tj
/T1_1 1 Tf
-0.005 Tc
4.536 0 Td
(\055hydroxylase) Tj
/Span <<
/ActualText (\376\377\000\240)
>> BDC
( ) Tj
EMC
<7f206d6f7573652066656564696e67206d6f64656c> Tj
-0.025 Tw
9.75 0 0 9.75 319 291.1881 Tm
(Nonalcoholic fatty liver disease \050NAFLD\051 is the most fre) Tj
0 Tc
0 Tw
(\055) Tj
0.02 Tc
0.058 Tw
-1.026 -1.205 Td
[ (quent liver disease in industrialized countries \0501\051\056 The) 20 ( ) ] TJ
0.01 Tc
0.115 Tw
0 -1.205 TD
[ (prevalence of NAFLD ranges from 11\045 to 46\045\054 with a) 10 ( ) ] TJ
/T1_0 1 Tf
-0.005 Tc
0.005 Tw
9.5 0 0 9.5 46 474.6311 Tm
(Abstract) Tj
/Span <<
/ActualText (\376\377 \003)
>> BDC
( ) Tj
EMC
0.136 Tw
4.535 0 Td
[ (Nonalcoholic steatohepatitis \050NASH\051\054 a primar) -55.9 (y) -5 ( ) ] TJ
0.071 Tw
-4.535 -1.105 Td
[ (cause of liver disease\054 leads to complications such as \037br) 15 (o) ] TJ
0 Tc
0 Tw
(\055) Tj
0.02 Tc
0.023 Tw
0 -1.105 TD
[ (sis\054 cir) -32 (r) 9 (hosis\054 and car) 14 (cinoma\054 but the pathophysiology of) 20 ( ) ] TJ
0.254 Tw
0 -1.105 TD
[ (NASH is incompletely understood\056 Epstein\055Bar) -32 (r vir) -28 (us\055) ] TJ
0 Tc
0 Tw
25.789 0 Td
( ) Tj
-0.02 Tc
-0.021 Tw
-25.789 -1.105 Td
[ (induced G pr) 15 (otein\055coupled r) 9 (eceptor 2 \050EBI2\051 and its oxyst) -15 (e) -15 (ro) -15 (l) -20 ( ) ] TJ
-0.01 Tc
0.006 Tw
T*
(ligand 7) Tj
/T1_2 1 Tf
0 Tc
0 Tw
(\037) Tj
/T1_0 1 Tf
-0.01 Tc
0.006 Tw
4.043 0 Td
[ (\05425\055dihydr) 15 (oxycholester) 15 (ol \0507) ] TJ
/T1_2 1 Tf
0 Tc
0 Tw
(\037) Tj
/T1_0 1 Tf
-0.01 Tc
0.006 Tw
12.283 0 Td
[ (\05425\055diHC\051 ar) 9 (e r) 9.1 (ecently) -10 ( ) ] TJ
-0.005 Tc
0.26 Tw
-16.326 -1.105 Td
[ (discover) 9 (ed immune r) 8.9 (egulators\056 Several lines of evidence) -5 ( ) ] TJ
-0.038 Tw
0 -1.105 TD
[ (suggest a r) 15 (ole of oxyster) 14.9 (ols in NASH pathogenesis\054 but rigor) ] TJ
0 Tc
0 Tw
(\055) Tj
-0.005 Tc
-0.004 Tw
0 -1.105 TD
[ (ous testing has not been per) -8.9 (for) -36 (med\056 W) 79 (e measur) 9 (ed oxyster) 15 (ol) -5 ( ) ] TJ
-0.046 Tw
T*
[ (levels in the livers of NASH patients by LC\055MS and tested the) -5 ( ) ] TJ
-0.02 Tc
-0.049 Tw
T*
(role of the EBI2\0557) Tj
/T1_2 1 Tf
0 Tc
0 Tw
(\037) Tj
/T1_0 1 Tf
-0.02 Tc
-0.049 Tw
7.941 0 Td
[ (\05425\055diHC system in a murine feeding model) -20 ( ) ] TJ
-0.005 Tc
0.064 Tw
-7.941 -1.105 Td
[ (of NASH\056 Fr) 9 (ee oxyster) 15 (ol pr) 15 (o\037ling in livers fr) 15 (om NASH pa) ] TJ
0 Tc
0 Tw
(\055) Tj
-0.03 Tc
-0.003 Tw
T*
[ (tients r) 9 (evealed a pr) 15 (onounced incr) 9 (ease in 24\055 and 7\055hydr) 15 (oxylated) -29.9 ( ) ] TJ
-0.02 Tc
-0.001 Tw
T*
[ (oxyster) 15 (ols in NASH compar) 9 (ed with contr) 15 (ols\056 Levels of 24\055 and) -20 ( ) ] TJ
-0.005 Tc
-0.019 Tw
0 -1.105 TD
[ (7\055hydr) 15 (oxylated oxyster) 15 (ols cor) -32 (r) 9 (elated with histological NASH) -4.9 ( ) ] TJ
-0.001 Tw
0 -1.105 TD
[ (activity) 70 (\056 ) 0.5 (Histological analysis ) 0.5 (of murine ) 0.5 (l) 15 (i) 15 (v) 15 (e) 15 (r) 15 ( ) 15.4 (s) 15 (a) 15 (m) 15 (p) 15 (l) 15 (e) 15 (s) 15 ( ) 15.5 (d) 15 (e) 15 (m) 15 (o) 15 (n) ] TJ
0 Tc
0 Tw
25.549 0 Td
(\055) Tj
-0.02 Tc
0.006 Tw
-25.549 -1.105 Td
[ (strated ballooning and liver in\036ammation\056) -15 ( ) -15.4 (N) -15 (o) -15 ( ) -15.4 (s) -14.9 (i) -15 (g) -15 (n) -15.1 (i) -15 (\037) -15 (c) -15 (a) -15 (n) -15 (t) -14.9 ( ) -15.4 (g) -15.1 (e) -15 (n) ] TJ
0 Tc
0 Tw
25.549 0 Td
(\055) Tj
-0.005 Tc
-0.041 Tw
-25.549 -1.105 Td
[ (otype\055r) 9 (elated dif) 34 (fer) 9 (ences wer) 9 (e obser) -56 (ved in ) ] TJ
/T1_3 1 Tf
0.008 Tc
-0.008 Tw
(Ebi2) Tj
/T1_6 1 Tf
0 Tc
0 Tw
6.175 0 0 6.175 239.0852 300.8811 Tm
(\037) Tj
/T1_3 1 Tf
0.828 0 Td
(\057) Tj
/T1_6 1 Tf
0.448 0 Td
(\037) Tj
/T1_0 1 Tf
-0.005 Tc
-0.041 Tw
9.5 0 0 9.5 252.0772 296.1311 Tm
[ ( mice and) -5 ( ) ] TJ
0.131 Tw
-21.692 -1.105 Td
(mice with defects in the 7) Tj
/T1_2 1 Tf
0 Tc
0 Tw
(\037) Tj
/T1_0 1 Tf
-0.005 Tc
0.131 Tw
12.287 0 Td
[ (\05425\055diHC synthesizing enzymes) -5 ( ) ] TJ
-0.01 Tc
-0.044 Tw
-12.287 -1.105 Td
[ (CH25H and CYP7B1 compar) 9 (ed with wild\055type litter) -36 (mate con) ] TJ
0 Tc
0 Tw
(\055) Tj
-0.02 Tc
0.011 Tw
T*
[ (tr) 15 (ols\054 ) 0.5 (ar) 5 (guing ) 0.5 (against ) 0.6 (an ) 0.5 (essential ) 0.5 (r) 15 (ole ) 0.6 (of ) 0.5 (these ) 0.5 (genes ) 0.6 (in ) 0.5 (NASH) -20 ( ) ] TJ
0.02 Tc
0.088 Tw
T*
[ (pathogenesis\056 Elevated 24\055 and 7\055hydr) 15 (oxylated oxyster) 15 (ol) 20 ( ) ] TJ
ET
0 0 0 0 scn
/GS1 gs
46 64.983 245 166.808 re
f
/CS0 CS
0 0 0 1 SCN
0.4 w
/GS0 gs
q
1 0 0 1 46 237.1833 cm
0 0 m
245 0 l
S
Q
BT
0 0 0 1 scn
/T1_4 1 Tf
-0.005 Tc
0.419 Tw
8 0 0 8 46 225.9834 Tm
[ (This work was supported by Swiss National Science Foundation Grant) -5 ( ) ] TJ
0.304 Tw
0 -1 TD
[ (32473B\137156525 \050B\056M\056\051\054 a grant from the Hartmann\055M\374ller Foundation) -5 ( ) ] TJ
0.031 Tw
T*
[ (\050B\056M\056\051\054 and UK Biotechnology and Biological ) 0.5 (Sciences Research Council Grant) -5 ( ) ] TJ
0.074 Tw
T*
(BB\057L001942\0571 \050Y\056W\056\051\056 The funding institutions had no role in the study de) Tj
0 Tc
0 Tw
(\055) Tj
-0.005 Tc
-0.016 Tw
T*
[ (sign\054 analysis\054 interpretation of the data\054 or in writing the manuscript\056 G\056R\056 was) -5 ( ) ] TJ
0.041 Tw
T*
(supported by grants from AbbVie\054 Ardeypharm\054 MSD\054 Falk\054 Flamentera\054 Novar) Tj
0 Tc
0 Tw
(\055) Tj
-0.005 Tc
0.047 Tw
T*
[ (tis\054 Roche\054 Tillots\054 UCB\054 and Zeller\056 P\056S\056 has received travel support from Falk\054) -5 ( ) ] TJ
-0.049 Tw
T*
[ (UCB\054 and P\037zer and an advisory board honorarium from P\037zer\056 B\056M\056 has served) -5 ( ) ] TJ
0.097 Tw
T*
[ (on an advisory board for Gilead and Novigenix\073 has received traveling fees or) -5 ( ) ] TJ
0.049 Tw
T*
[ (speaking fees from Given Imaging\054 MSD\054 Vifor\054 and Novartis and has received) -5 ( ) ] TJ
0.115 Tw
T*
[ (an unrestricted research ) 0.5 (grant from MSD\056 ) 0.5 (A\056G\056 serves as a ) 0.5 (steering committee) -5 ( ) ] TJ
0.053 Tw
T*
[ (member ) 0.5 (for Gilead\054 ) 0.5 (Intercept\054 ) 0.5 (and ) 0.5 (Novartis\054 advisor ) 0.5 (for ) 0.5 (AbbVie\054 ) 0.5 (Alexion\054 ) 0.5 (BMS\054) -5 ( ) ] TJ
-0.02 Tc
-0.037 Tw
T*
[ (Gilead\054 ) 0.5 (Intercept\054 Ipsen\054 ) 0.5 (Novartis\054 P\037zer\054 ) 0.5 (and ) 0.5 (Sequana\054 speaker ) 0.5 (for ) 0.5 (AbbVie\054 Alexion\054) -20 ( ) ] TJ
-0.005 Tc
0.012 Tw
T*
[ (BMS\054 ) 0.5 (CSL Behring\054 ) 0.5 (Falk\054 ) 0.5 (Gilead\054 ) 0.5 (Intercept\054 ) 0.5 (Merz\054 Novartis\054 ) 0.5 (and Sequana\054 ) 0.5 (and) -5 ( ) ] TJ
0.061 Tw
T*
[ (has received research grants from Exalenz \050Liver Investigation\072 Testing Marker) -5 ( ) ] TJ
0.013 Tw
T*
[ (Utility ) 0.5 (in Steatohepatitis\073 LITMUS\051\054 ) 0.5 (Intercept ) 0.5 (\050Nonalcoholic ) 0.5 (Fatty ) 0.5 (Liver Disease) -5 ( ) ] TJ
0 Tw
T*
(Clinical Study Group\073 NAFLD CSG\051\054 Novartis\054 and Kibion\056) Tj
-0.01 Tc
0 -1.5 TD
[ (Manuscript r) 18 (eceived 26 Febr) -15 (uar) -50 (y 2019 and in r) 18 (evised for) -9.9 (m 19 May 2019\056) ] TJ
-0.005 Tc
T*
(Published\054 JLR Papers in Press\054 May 21\054 2019) Tj
0 -1.125 TD
(DOI https\072\057\057doi\056org\05710\0561194\057jlr\056M093229) Tj
/T1_7 1 Tf
19 0 0 19 70 679.5661 Tm
[ (Elevated oxyster) 17.9 (ol levels in human and mouse livers) -5 ( ) ] TJ
0 -1.263 TD
[ (r) 18 (e\037ect nonalcoholic steatohepatitis) ] TJ
ET
q
/GS1 gs
6.264 0 0 6.192 362.25174 663.56612 cm
/Im1 Do
Q
BT
/T1_0 1 Tf
10 0 0 10 130 623.5661 Tm
[ (T) 1 (ina Raselli\054) ] TJ
0.005 Tw
6.5 0 0 6.5 183.9397 628.5661 Tm
(1\054) Tj
0 Tw
10 0 0 10 189.0746 623.5661 Tm
[ (\052 T) 82 (om Hear) -35 (n\054) ] TJ
0 Tc
6.5 0 0 6.5 249.6041 628.5661 Tm
(\206) Tj
-0.005 Tc
10 0 0 10 252.9515 623.5661 Tm
[ ( Annika W) 12 (yss\054\052 Kirstin Atr) 15 (ott\054\052 Alain Peter) 71 (\054\052 Isabelle Fr) 9 (ey\055W) 55 (agner) 71 (\054\052) -5 ( ) ] TJ
-12.295 -1.1 Td
[ (Marianne R\056 Spalinger) 71 (\054\052 Ewer) -23 (ton M\056 Maggio\054\247 Andr) 9 (eas W) 69 (\056 Sailer) 70.9 (\054\052\052 Johannes Schmitt\054) ] TJ
0.005 Tw
6.5 0 0 6.5 499.3265 617.5661 Tm
(\206\206) Tj
0 Tc
0 Tw
10 0 0 10 506.0539 612.5661 Tm
( ) Tj
0.252 0 Td
( ) Tj
-0.005 Tc
-37.857 -1.1 Td
[ (Philipp Schr) 9 (einer) 71 (\054\052 Anja Moncsek\054\052 Joachim Mer) -23 (tens\054\052 Michael Scharl\054\052 W) -12 (illiam J\056 Grif\037ths\054) ] TJ
0 Tc
6.5 0 0 6.5 528.2458 606.5661 Tm
(\206) Tj
10 0 0 10 531.6257 601.5661 Tm
( ) Tj
-0.005 Tc
-40.163 -1.1 Td
[ (Mar) 14 (co Bueter) 71 (\054\247\247 Andr) 9 (eas Geier) 71 (\054) ] TJ
0.005 Tw
6.5 0 0 6.5 268.0488 595.5661 Tm
(\206\206) Tj
0 Tw
10 0 0 10 274.7437 590.5661 Tm
[ ( Ger) 9 (har) 10 (d Rogler) 71 (\054\052 Y) 43 (uqin W) 55 (ang\054) ] TJ
0 Tc
6.5 0 0 6.5 409.0128 595.5661 Tm
(\206) Tj
-0.005 Tc
10 0 0 10 412.3602 590.5661 Tm
( and Benjamin Misselwitz) Tj
0.005 Tw
6.5 0 0 6.5 521.1591 595.5661 Tm
(2\054) Tj
0 Tc
0 Tw
10 0 0 10 526.2939 590.5661 Tm
(\052) Tj
6.5 0 0 6.5 531.4438 595.5661 Tm
(\054) Tj
-0.005 Tc
0.005 Tw
10 0 0 10 533.2313 590.5661 Tm
(\052\052\052) Tj
/T1_1 1 Tf
0 Tw
9 0 0 9 130 574.5661 Tm
[ (Department of Gastroenterology and Hepatology) 73.9 (\054\052 Department of Visceral Surger) -20 (y) 74 (\054) ] TJ
0.005 Tw
5.85 0 0 5.85 453.0688 579.0661 Tm
(\247\247) Tj
0 Tw
9 0 0 9 458.8603 574.5661 Tm
[ ( and Institute for) -5.1 ( ) ] TJ
-36.54 -1.222 Td
[ (Surgical Pathology) 74 (\054) ] TJ
0 Tc
5.85 0 0 5.85 203.718 568.0661 Tm
(\247) Tj
-0.005 Tc
9 0 0 9 206.6138 563.5661 Tm
[ ( University Hospital Zurich and University of Zurich\054 Zurich\054 Switzerland\073 Swansea) -5 ( ) ] TJ
-8.513 -1.222 Td
(University Medical School\054) Tj
0 Tc
5.85 0 0 5.85 233.0488 557.0661 Tm
(\206) Tj
-0.005 Tc
9 0 0 9 235.9445 552.5661 Tm
[ ( Singleton Park\054 Swansea\054 United Kingdom\073 Chemical Biology and) -5 ( ) ] TJ
-11.772 -1.222 Td
[ (Therapeutics\054\052\052 Novartis Institutes for BioMedical Research\054 Basel\054 Switzerland\073 Division of Hepatology) 74 (\054) ] TJ
0.005 Tw
5.85 0 0 5.85 530.5486 546.0661 Tm
(\206\206) Tj
0 Tc
0 Tw
9 0 0 9 536.3694 541.5661 Tm
( ) Tj
-0.005 Tc
-45.152 -1.222 Td
[ (Department of Internal Medicine II\054 University Hospital W\374rzburg\054 W\374rzburg\054 Germany\073 and Department of) -5 ( ) ] TJ
0 -1.222 TD
[ (Visceral Surger) -20 (y and Medicine\054\052\052\052 Inselspital Bern and Bern University) 74 (\054 Bern\054 Switzerland) ] TJ
0 -2 TD
[ (ORCID IDs\072 0000\0550002\0554129\0556616 \050W) 55 (\056J\056G\056\051\073 0000\0550002\0553063\0553066 \050Y) 90 (\056G\056\051\073 0000\0550002\0558719\055517 \050B\056M\056\051) ] TJ
ET
q
1 0 0 1 309 245.2 cm
0 0 m
36 0 l
S
Q
BT
/T1_1 1 Tf
-0.01 Tc
0.009 Tw
8 0 0 8 319 227 Tm
(Abbreviations\072) Tj
/Span <<
/ActualText (\376\377 \003)
>> BDC
( ) Tj
EMC
7.09 0 Td
(ALT\054 alanine transaminase\073 AST\054 aspartate transami) Tj
0 Tc
0 Tw
(\055) Tj
-0.02 Tc
-0.05 Tw
-8.34 -1.125 Td
[ (nase\073 ) 0.5 (EBI2\054 ) 0.5 (Epstein\055Barr ) 0.5 (virus\055induced ) 0.5 (G ) 0.5 (protein ) 0.5 (coupled ) 0.5 (receptor ) 0.5 (2\073 ) 0.6 (H\057E\054) -19.9 ( ) ] TJ
0.151 Tw
0 -1.125 TD
[ (hematoxylin\057eosin\073 HFD\054 high\055fat diet\073 LXR\054 liver X receptor\073 NAFLD\054) -20 ( ) ] TJ
0.014 Tw
T*
(nonalcoholic fatty liver disease\073 NAS\054 NAFLD activity score\073 NASH\054 nonal) Tj
0 Tc
0 Tw
(\055) Tj
-0.02 Tc
0.059 Tw
T*
(coholic steatohepatitis\073 STD\054 standard diet\073 6\055HC\054 cholest\0555\055ene\0553) Tj
/T1_5 1 Tf
0 Tc
0 Tw
(\036) Tj
/T1_1 1 Tf
-0.02 Tc
0.02 Tw
27.785 0 Td
[ (\0546\055diol\073) -20 ( ) ] TJ
0 Tc
0 Tw
-27.785 -1.125 Td
(7) Tj
/T1_5 1 Tf
0.54 0 Td
(\037) Tj
/T1_1 1 Tf
0.02 Tc
-0.02 Tw
0.631 0 Td
(\05412) Tj
/T1_5 1 Tf
0 Tc
0 Tw
(\037) Tj
/T1_1 1 Tf
0.02 Tc
-0.011 Tw
1.991 0 Td
(\055diHC\054 cholest\0555\055ene\0553) Tj
/T1_5 1 Tf
0 Tc
0 Tw
(\036) Tj
/T1_1 1 Tf
0.02 Tc
-0.02 Tw
10.62 0 Td
(\0547) Tj
/T1_5 1 Tf
0 Tc
0 Tw
(\037) Tj
/T1_1 1 Tf
0.02 Tc
-0.02 Tw
1.451 0 Td
(\05412) Tj
/T1_5 1 Tf
0 Tc
0 Tw
(\037) Tj
/T1_1 1 Tf
0.02 Tc
-0.011 Tw
1.991 0 Td
(\055triol\073 7) Tj
/T1_5 1 Tf
0 Tc
0 Tw
(\037) Tj
/T1_1 1 Tf
0.02 Tc
-0.02 Tw
3.92 0 Td
(\05412) Tj
/T1_5 1 Tf
0 Tc
0 Tw
(\037) Tj
/T1_1 1 Tf
0.02 Tc
-0.011 Tw
1.991 0 Td
(\055diHCO\054 7) Tj
/T1_5 1 Tf
0 Tc
0 Tw
(\037) Tj
/T1_1 1 Tf
0.02 Tc
-0.02 Tw
5.26 0 Td
(\05412) Tj
/T1_5 1 Tf
0 Tc
0 Tw
(\037) Tj
/T1_1 1 Tf
1.991 0 Td
(\055) Tj
-0.01 Tc
-0.009 Tw
-30.385 -1.125 Td
(dihydroxycholest\0554\055en\0553\055one\073 7) Tj
/T1_5 1 Tf
0 Tc
0 Tw
(\037) Tj
/T1_1 1 Tf
-0.01 Tc
-0.009 Tw
13.532 0 Td
(\05424S\055diHC\054 cholest\0555\055ene\0553) Tj
/T1_5 1 Tf
0 Tc
0 Tw
(\036) Tj
/T1_1 1 Tf
-0.01 Tc
0.01 Tw
11.712 0 Td
(\0547) Tj
/T1_5 1 Tf
0 Tc
0 Tw
(\037) Tj
/T1_1 1 Tf
-0.01 Tc
0.01 Tw
1.361 0 Td
(\05424) Tj
/T1_4 1 Tf
0 Tc
0 Tw
(S) Tj
/T1_1 1 Tf
-0.01 Tc
0.01 Tw
1.74 0 Td
[ (\055triol\073) -10 ( ) ] TJ
0 Tc
0 Tw
-28.345 -1.125 Td
(7) Tj
/T1_5 1 Tf
0.54 0 Td
(\037) Tj
/T1_1 1 Tf
0.02 Tc
-0.063 Tw
0.631 0 Td
(\05425\055diHC\054 cholest\0555\055ene\0553) Tj
/T1_5 1 Tf
0 Tc
0 Tw
(\036) Tj
/T1_1 1 Tf
0.02 Tc
-0.02 Tw
11.928 0 Td
(\0547) Tj
/T1_5 1 Tf
0 Tc
0 Tw
(\037) Tj
/T1_1 1 Tf
0.02 Tc
-0.063 Tw
1.451 0 Td
(\05425\055triol\073 7) Tj
/T1_5 1 Tf
0 Tc
0 Tw
(\037) Tj
/T1_1 1 Tf
0.02 Tc
-0.063 Tw
5.228 0 Td
(\05427\055diHCO\054 7) Tj
/T1_5 1 Tf
0 Tc
0 Tw
(\037) Tj
/T1_1 1 Tf
0.02 Tc
-0.02 Tw
6.568 0 Td
(\054\05025R\05126\055) Tj
-0.01 Tc
0.114 Tw
-26.345 -1.125 Td
(dihydroxycholest\0554\055en\0553\055one\073 7) Tj
/T1_5 1 Tf
0 Tc
0 Tw
(\037) Tj
/T1_1 1 Tf
-0.01 Tc
0.114 Tw
13.655 0 Td
(\055HC\054 cholest\0555\055ene\0553) Tj
/T1_5 1 Tf
0 Tc
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