{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T01:41:45Z","timestamp":1790041305388,"version":"4.0.1"},"reference-count":33,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","license":[{"start":{"date-parts":[[2020,3,24]],"date-time":"2020-03-24T00:00:00Z","timestamp":1585008000000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Hepatol Commun"],"published-print":{"date-parts":[[2020,5]]},"abstract":"<jats:p>Hyperactivation of sterol regulatory element binding protein 1c (SREBP\u20101c), which transcriptionally induces expression of enzymes responsible for <jats:italic toggle=\"yes\">de novo<\/jats:italic> lipogenesis and triglyceride (TG) formation, is implicated in nonalcoholic fatty liver disease (NAFLD)\/nonalcoholic steatohepatitis (NASH) pathogenesis. Posttranslational SREBP\u20101c maturation and activation is stimulated by the protein per\u2013arnt\u2013sim kinase (PASK). <jats:italic toggle=\"yes\">PASK\u2010<\/jats:italic>knockout mice are phenotypically normal on a conventional diet but exhibit decreased hypertriglyceridemia, insulin resistance, and hepatic steatosis on a high\u2010fat diet. We investigated the effects of pharmacologic PASK inhibition using BioE\u20101115, a selective and potent oral PASK inhibitor, in Zucker fatty (<jats:italic toggle=\"yes\">fa<\/jats:italic>)<jats:italic toggle=\"yes\">\/fa)<\/jats:italic> rats, a genetic model of obesity, dyslipidemia, and insulin resistance, and in a dietary murine model of NAFLD\/NASH. Female Zucker (<jats:italic toggle=\"yes\">fa\/fa<\/jats:italic>) rats and lean littermate (<jats:italic toggle=\"yes\">fa<\/jats:italic>\/+) controls received BioE\u20101115 (3\u2010100\u00a0mg\/kg\/day) and\/or omega\u20103 fatty acids, and blood glucose, hemoglobin A1c, glucose tolerance, insulin, and serum TG were measured. C57BL\/6J mice fed a high\u2010fat\/high\u2010fructose diet (HF\u2010HFrD) were treated with BioE\u20101115 (100\u00a0mg\/kg\/day) or vehicle. Body weight and fasting glucose were measured regularly; serum TG, body and organ weights, and liver TG and histology were assessed at sacrifice. Messenger RNA (mRNA) abundance of SREBP\u20101c target genes was measured in both models. In Zucker rats, BioE\u20101115 treatment produced significant dose\u2010dependent reductions in blood glucose, insulin, and TG (all greater than omega\u20103 fatty acids) and dose dependently restored insulin sensitivity assessed by glucose tolerance testing. In HF\u2010HFrD mice, BioE\u20101115 reduced body weight, liver weight, fasting blood glucose, serum TGs, hepatic TG, hepatic fibrosis, hepatocyte vacuolization, and bile duct hyperplasia. BioE\u20101115 reduced SREBP\u20101c target mRNA transcripts in both models. <jats:italic toggle=\"yes\">Conclusion:<\/jats:italic> PASK inhibition mitigates many adverse metabolic consequences associated with an HF\u2010HFrD and reduces hepatic fat content and fibrosis. This suggests that inhibition of PASK is an attractive therapeutic strategy for NAFLD\/NASH treatment.<\/jats:p>","DOI":"10.1002\/hep4.1498","type":"journal-article","created":{"date-parts":[[2020,3,24]],"date-time":"2020-03-24T09:25:09Z","timestamp":1585041909000},"page":"696-707","source":"Crossref","is-referenced-by-count":11,"title":["Validation of PAS Kinase, a Regulator of Hepatic Fatty Acid and Triglyceride Synthesis, as a Therapeutic Target for Nonalcoholic Steatohepatitis"],"prefix":"10.1097","volume":"4","author":[{"given":"Wojciech","family":"Swiatek","sequence":"first","affiliation":[{"name":"Department of Biochemistry,University of Utah School of Medicine,University of Utah,Salt Lake City,UT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K. Mark","family":"Parnell","sequence":"additional","affiliation":[{"name":"BioEnergenix, LLC,San Francisco,CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G. Allen","family":"Nickols","sequence":"additional","affiliation":[{"name":"BioEnergenix, LLC,San Francisco,CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce F.","family":"Scharschmidt","sequence":"additional","affiliation":[{"name":"BioEnergenix, LLC,San Francisco,CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jared","family":"Rutter","sequence":"additional","affiliation":[{"name":"Department of Biochemistry,University of Utah School of Medicine,University of Utah,Salt Lake City,UT"},{"name":"Howard Hughes Medical Institute,Salt Lake City,UT"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2020,3,24]]},"reference":[{"key":"hep41498-bib-0001-20240114","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1002\/hep.28524","article-title":"The globalization of nonalcoholic fatty liver disease: Prevalence and impact on world 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