{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T01:21:55Z","timestamp":1787016115423,"version":"build-2736575974"},"reference-count":53,"publisher":"Wiley","issue":"18","license":[{"start":{"date-parts":[[2016,5,27]],"date-time":"2016-05-27T00:00:00Z","timestamp":1464307200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2016,9,15]]},"abstract":"<jats:sec>\n                    <jats:title>Key points<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>Physiologically relevant rodent models of non\u2010alcoholic steatohepatitis (NASH) that resemble the human condition are limited.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Exercise training and energy restriction are first\u2010line recommendations for the treatment of NASH.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Hyperphagic Otsuka Long\u2013Evans Tokushima fatty rats fed a western diet high in fat, sucrose and cholesterol for 24\u00a0weeks developed a severe NASH with fibrosis phenotype.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Moderate intensity exercise training and modest energy restriction provided some improvement in the histological features of NASH that coincided with alterations in markers of hepatic stellate cell activation and extracellular matrix remodelling.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>The present study highlights the importance of lifestyle modification, including exercise training and energy restriction, in the regulation of advanced liver disease.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Abstract<\/jats:title>\n                    <jats:p>\n                      The incidence of non\u2010alcoholic steatohepatitis (NASH) is rising but the efficacy of lifestyle modifications to improve NASH\u2010related outcomes remain unclear. We hypothesized that a western diet (WD) would induce NASH in the Otsuka Long\u2013Evans Tokushima Fatty (OLETF) rat and that lifestyle modification would improve this condition. Eight\u2010week\u2010old Long\u2013Evans Tokushima Otsuka (L) and OLETF (O) rats consumed a control diet (10%\u00a0kcal fat, 3.5% sucrose) or a WD (45%\u00a0kcal fat, 17% sucrose, 1% cholesterol) for 24\u00a0weeks. At 20\u00a0weeks of age, additional WD\u2010fed OLETFs were randomized to sedentary (O\u2010SED), food restriction (O\u2010FR; \u223c25% kcal reduction\n                      <jats:italic>vs<\/jats:italic>\n                      . O\u2010SED) or exercise training (O\u2010EX; treadmill running 20\u00a0m\u00a0min\n                      <jats:sup>\u20131<\/jats:sup>\n                      with a 15% incline, 60\u00a0min\u00a0day\n                      <jats:sup>\u20131<\/jats:sup>\n                      , 5\u00a0days\u00a0week\n                      <jats:sup>\u20131<\/jats:sup>\n                      ) conditions for 12\u00a0weeks. WD induced a NASH phenotype in OLETFs characterized by hepatic fibrosis (collagen 1\u03b11 mRNA and hydroxyproline content), as well as elevated inflammation and non\u2010alcoholic fatty liver disease activity scores, and hepatic stellate cell activation (\u03b1\u2010smooth muscle actin) compared to Long\u2013Evans Tokushima Otsuka rats. FR and EX modestly improved NASH\u2010related fibrosis markers (FR: hydroxyproline content,\n                      <jats:italic>P\u00a0&lt;\u00a0<\/jats:italic>\n                      0.01; EX: collagen 1\u03b11 mRNA,\n                      <jats:italic>P\u00a0&lt;\u00a0<\/jats:italic>\n                      0.05; both: fibrosis score,\n                      <jats:italic>P\u00a0&lt;\u00a0<\/jats:italic>\n                      0.01) and inflammation (both: inflammation score; FR: interleukin\u20101\u03b2 and tumor necrosis factor \u03b1)\n                      <jats:italic>vs<\/jats:italic>\n                      . O\u2010SED. FR reduced hepatic stellate cell activation markers (transforming growth factor\u2010\u03b2 protein and \u03b1\u2010smooth muscle actin mRNA), whereas EX increased the hepatic stellate cell senescence marker CCN1 (\n                      <jats:italic>P\u00a0&lt;\u00a0<\/jats:italic>\n                      0.01\u00a0\n                      <jats:italic>vs<\/jats:italic>\n                      . O\u2010SED). Additionally, both FR and EX normalized extracellular matrix remodelling markers to levels similar to L\u2010WD (\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0&gt;\u00a00.05). Although neither EX nor FR led to complete resolution of the WD\u2010induced NASH phenotype, both independently benefitted liver fibrosis via altered hepatic stellate cell activation and extracellular matrix remodelling.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1113\/jp272235","type":"journal-article","created":{"date-parts":[[2016,4,22]],"date-time":"2016-04-22T18:47:04Z","timestamp":1461350824000},"page":"5271-5284","source":"Crossref","is-referenced-by-count":56,"title":["Aerobic exercise training in the treatment of non\u2010alcoholic fatty liver disease related fibrosis"],"prefix":"10.1113","volume":"594","author":[{"given":"Melissa A.","family":"Linden","sequence":"first","affiliation":[{"name":"Research Service Harry S Truman Memorial VA Hospital"},{"name":"Department of Nutrition and Exercise Physiology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan D.","family":"Sheldon","sequence":"additional","affiliation":[{"name":"Research Service Harry S Truman Memorial VA Hospital"},{"name":"Department of Nutrition and Exercise Physiology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grace M.","family":"Meers","sequence":"additional","affiliation":[{"name":"Research Service Harry S Truman Memorial VA Hospital"},{"name":"Department of Medicine\u2010Division of Gastroenterology and Hepatology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura C.","family":"Ortinau","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Exercise Physiology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E. Matthew","family":"Morris","sequence":"additional","affiliation":[{"name":"Department of Molecular and Integrative Physiology University of Kansas Medical Centre  Kansas City KS USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank W.","family":"Booth","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences"},{"name":"Department of Medical Pharmacology and Physiology"},{"name":"Dalton Cardiovascular Research Centre"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jill A.","family":"Kanaley","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Exercise Physiology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria J.","family":"Vieira\u2010Potter","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Exercise Physiology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James R.","family":"Sowers","sequence":"additional","affiliation":[{"name":"Research Service Harry S Truman Memorial VA Hospital"},{"name":"Medicine\u2010Division of Endocrinology University of Missouri  Columbia MO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jamal A.","family":"Ibdah","sequence":"additional","affiliation":[{"name":"Research Service Harry S Truman Memorial VA Hospital"},{"name":"Department of Medicine\u2010Division of Gastroenterology and Hepatology"},{"name":"Department of Medical Pharmacology and Physiology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John P.","family":"Thyfault","sequence":"additional","affiliation":[{"name":"Department of Molecular and Integrative Physiology University of Kansas Medical Centre  Kansas City KS USA"},{"name":"Kansas City VA Medical Centre  Kansas City MO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. 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