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AD, the most common cause of dementia, is increasingly considered as a metabolic disease, although underlying pathogenic mechanisms remain unclear. The liver plays a major role in maintaining glucose and lipid homeostasis, as well as in clearing the AD neuropathogenic factor amyloid\u2010\u03b2 (A\u03b2) and in metabolizing cerebrosterol, a cerebral\u2010derived oxysterol proposed as an AD biomarker. We hypothesized that liver impairment induced by obesity contributes to AD pathogenesis. We show that the AD triple transgenic mouse model (3xTg\u2010AD) fed a chow diet presents a hepatic phenotype similar to nontransgenic controls (NTg) at 15\u00a0months of age. A high\u2010fat diet (HFD), started at the age of 6\u00a0months and continued for 9\u00a0months, until sacrifice, induced hepatic steatosis in NTg, but not in 3xTg\u2010AD mice, whereas HFD did not induce changes in hepatic fatty acid oxidation, <jats:italic toggle=\"yes\">de novo<\/jats:italic> lipogenesis, and gluconeogenesis. HFD\u2010induced obesity was associated with a reduction of insulin\u2010degrading enzyme, one of the main hepatic enzymes responsible for A\u03b2 clearance. The hepatic rate of cerebrosterol glucuronidation was lower in obese 3xTg\u2010AD than in nonobese controls (<jats:italic toggle=\"yes\">P<\/jats:italic>\u00a0&lt;\u00a00.05) and higher compared with obese NTg (<jats:italic toggle=\"yes\">P<\/jats:italic>\u00a0&lt;\u00a00.05), although circulating levels remained unchanged. <jats:italic toggle=\"yes\">Conclusion:<\/jats:italic> Modulation of hepatic lipids, A\u03b2, and cerebrosterol metabolism in obese 3xTg\u2010AD mice differs from control mice. This study sheds light on the liver\u2013brain axis, showing that the chronic presence of NAFLD and changes in liver function affect peripheral AD features and should be considered during development of biomarkers or AD therapeutic targets.<\/jats:p>","DOI":"10.1002\/hep4.1609","type":"journal-article","created":{"date-parts":[[2020,12,18]],"date-time":"2020-12-18T17:30:47Z","timestamp":1608312647000},"page":"446-460","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":34,"title":["High\u2010Fat Diet Modulates Hepatic Amyloid \u03b2 and Cerebrosterol Metabolism in the Triple Transgenic Mouse Model of Alzheimer\u2019s Disease"],"prefix":"10.1097","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2235-6019","authenticated-orcid":false,"given":"Cristina R.","family":"Bosoi","sequence":"first","affiliation":[{"name":"Centre De Recherche De L\u2019institut De Cardiologie Et Pneumologie De Qu\u00e9bec,Qu\u00e9bec,Canada"},{"name":"Facult\u00e9 De M\u00e9decine,Universit\u00e9 Laval,Qu\u00e9bec,Canada"},{"name":"Axe Neurosciences,Centre De Recherche du CHU de Qu\u00e9bec\u2010Universit\u00e9 Laval,Qu\u00e9bec,Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mil\u00e8ne","family":"Vandal","sequence":"additional","affiliation":[{"name":"Axe Neurosciences,Centre De Recherche du CHU de Qu\u00e9bec\u2010Universit\u00e9 Laval,Qu\u00e9bec,Canada"},{"name":"Facult\u00e9 De Pharmacie,Universit\u00e9 Laval,Qu\u00e9bec,Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marine","family":"Tournissac","sequence":"additional","affiliation":[{"name":"Axe Neurosciences,Centre De Recherche du CHU de Qu\u00e9bec\u2010Universit\u00e9 Laval,Qu\u00e9bec,Canada"},{"name":"Facult\u00e9 De Pharmacie,Universit\u00e9 Laval,Qu\u00e9bec,Canada"},{"name":"OptiNutriBrain International Associated Laboratory,Qu\u00e9bec,Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manon","family":"Leclerc","sequence":"additional","affiliation":[{"name":"Axe Neurosciences,Centre De Recherche du CHU de Qu\u00e9bec\u2010Universit\u00e9 Laval,Qu\u00e9bec,Canada"},{"name":"Facult\u00e9 De Pharmacie,Universit\u00e9 Laval,Qu\u00e9bec,Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hortense","family":"Fanet","sequence":"additional","affiliation":[{"name":"Axe Neurosciences,Centre De Recherche du CHU de Qu\u00e9bec\u2010Universit\u00e9 Laval,Qu\u00e9bec,Canada"},{"name":"Facult\u00e9 De Pharmacie,Universit\u00e9 Laval,Qu\u00e9bec,Canada"},{"name":"OptiNutriBrain International Associated Laboratory,Qu\u00e9bec,Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia L.","family":"Mitchell","sequence":"additional","affiliation":[{"name":"Centre De Recherche De L\u2019institut De Cardiologie Et Pneumologie De Qu\u00e9bec,Qu\u00e9bec,Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M\u00e9lanie","family":"Verreault","sequence":"additional","affiliation":[{"name":"Laboratoire de Pharmacologie Mol\u00e9culaire,Axe Endocrinologie et N\u00e9phrologie,Centre de Recherche du CHU de Qu\u00e9bec (Pavillon CHUL),Qu\u00e9bec,Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jocelyn","family":"Trottier","sequence":"additional","affiliation":[{"name":"Laboratoire de Pharmacologie Mol\u00e9culaire,Axe Endocrinologie et N\u00e9phrologie,Centre de Recherche du CHU de Qu\u00e9bec (Pavillon CHUL),Qu\u00e9bec,Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica","family":"Virgili","sequence":"additional","affiliation":[{"name":"Axe Neurosciences,Centre De Recherche du CHU de Qu\u00e9bec\u2010Universit\u00e9 Laval,Qu\u00e9bec,Canada"},{"name":"Facult\u00e9 De Pharmacie,Universit\u00e9 Laval,Qu\u00e9bec,Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cynthia","family":"Tremblay","sequence":"additional","affiliation":[{"name":"Axe Neurosciences,Centre De Recherche du CHU de Qu\u00e9bec\u2010Universit\u00e9 Laval,Qu\u00e9bec,Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H. 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