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Phylogenetic analysis revealed conserved genetic evolution of SHP, FXR, CYP7A1, and CYP8B1. Shp, although primarily studied as a downstream target of Farnesoid X Receptor (Fxr), has a distinct hepatic role that is poorly understood. Here, we report that liver-specific Shp knockout (LShpKO) mice have impaired negative feedback of Cyp7a1 and Cyp8b1 on bile acid challenge and demonstrate that a single copy of the Shp gene is sufficient to maintain this response. LShpKO mice also exhibit elevated total bile acid pool with ileal bile acid composition mimicking that of cholic acid-fed control mice. Agonistic activation of Fxr (GW4064) in the LShpKO did not alter the elevated basal expression of Cyp8b1 but lowered Cyp7a1 expression. We found that deletion of Shp led to an enrichment of distinct motifs and pathways associated with circadian rhythm, copper ion transport, and DNA synthesis. We confirmed increased expression of metallothionein genes that can regulate copper levels in the absence of SHP. LShpKO livers also displayed a higher basal proliferation that was exacerbated specifically with bile acid challenge either with cholic acid or 3,5-diethoxycarbonyl-1,4-dihydrocollidine but not with another liver mitogen, 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene. Overall, our data indicate that hepatic SHP uniquely regulates certain proliferative and metabolic cues.<\/jats:p>","DOI":"10.1210\/endocr\/bqac052","type":"journal-article","created":{"date-parts":[[2022,4,22]],"date-time":"2022-04-22T05:41:47Z","timestamp":1650606107000},"source":"Crossref","is-referenced-by-count":7,"title":["Loss of Hepatic Small Heterodimer Partner Elevates Ileal Bile Acids and Alters Cell Cycle-related Genes in Male Mice"],"prefix":"10.1210","volume":"163","author":[{"given":"Ryan Philip Henry","family":"Shaw","sequence":"first","affiliation":[{"name":"Department of Molecular and Integrative Physiology, Urbana, IL 61801, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter","family":"Kolyvas","sequence":"additional","affiliation":[{"name":"Department of Molecular and Integrative Physiology, Urbana, IL 61801, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nathanlown","family":"Dang","sequence":"additional","affiliation":[{"name":"Department of Molecular and Integrative Physiology, Urbana, IL 61801, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Angela","family":"Hyon","sequence":"additional","affiliation":[{"name":"Department of Molecular and Integrative Physiology, Urbana, IL 61801, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Keith","family":"Bailey","sequence":"additional","affiliation":[{"name":"Veterinary Diagnostic Laboratory, Urbana, IL 61801, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2819-695X","authenticated-orcid":false,"given":"Sayeepriyadarshini","family":"Anakk","sequence":"additional","affiliation":[{"name":"Department of Molecular and Integrative Physiology, Urbana, IL 61801, USA"},{"name":"Beckman Institute for Advanced Science and Technology, Urbana, IL 61801, USA"},{"name":"Division of Nutritional Sciences, Urbana, IL 61801, USA"},{"name":"Cancer Center at Illinois, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"80","published-online":{"date-parts":[[2022,4,22]]},"reference":[{"key":"2022051715442794500_CIT0001","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1111\/liv.13682","article-title":"Liver diseases: a major, neglected global public health problem requiring urgent actions and large-scale screening","volume":"38","author":"Marcellin","year":"2018","journal-title":"Liver Int."},{"key":"2022051715442794500_CIT0002","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1186\/s12916-014-0159-5","article-title":"The global burden of liver disease: a challenge for methods and for public health","volume":"12","author":"Byass","year":"2014","journal-title":"BMC 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