title: Keratin 8 absence down-regulates colonocyte HMGCS2 and modulates colonic ketogenesis and energy metabolism.
abstract: Simple-type epithelial keratins are intermediate filament proteins important for mechanical stability and stress protection. Keratin mutations predispose to human liver disorders, whereas their roles in intestinal diseases are unclear. Absence of keratin 8 (K8) in mice leads to colitis, decreased Na/Cl uptake, protein mistargeting, and longer crypts, suggesting that keratins contribute to intestinal homeostasis. We describe the rate-limiting enzyme of the ketogenic energy metabolism pathway, mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), as a major down-regulated protein in the K8-knockout (K8(-/-)) colon. K8 absence leads to decreased quantity and activity of HMGCS2, and the down-regulation is not dependent on the inflammatory state, since HMGCS2 is not decreased in dextran sulfate sodium-induced colitis. Peroxisome proliferator-activated receptor α, a transcriptional activator of HMGCS2, is similarly down-regulated. Ketogenic conditions-starvation or ketogenic diet-increase K8(+/+) HMGCS2, whereas this response is blunted in the K8(-/-) colon. Microbiota-produced short-chain fatty acids (SCFAs), substrates in the colonic ketone body pathway, are increased in stool, which correlates with decreased levels of their main transporter, monocarboxylate transporter 1 (MCT1). Microbial populations, including the main SCFA-butyrate producers in the colon, were not altered in the K8(-/-). In summary, the regulation of the SCFA-MCT1-HMGCS2 axis is disrupted in K8(-/-) colonocytes, suggesting a role for keratins in colonocyte energy metabolism and homeostasis.
authors.affiliation: Cell Biology/Biosciences, Faculty of Science and Engineering, Åbo Akademi University, Turku 20520, Finland.
authors.forename: Terhi O
authors.initials: TO
authors.lastname: Helenius
authors.affiliation: Cell Biology/Biosciences, Faculty of Science and Engineering, Åbo Akademi University, Turku 20520, Finland.
authors.forename: Julia O
authors.initials: JO
authors.lastname: Misiorek
authors.affiliation: Cell Biology/Biosciences, Faculty of Science and Engineering, Åbo Akademi University, Turku 20520, Finland.
authors.forename: Joel H
authors.initials: JH
authors.lastname: Nyström
authors.affiliation: Cell Biology/Biosciences, Faculty of Science and Engineering, Åbo Akademi University, Turku 20520, Finland.
authors.forename: Lina E
authors.initials: LE
authors.lastname: Fortelius
authors.affiliation: Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Palo Alto, CA 94305.
authors.forename: Aida
authors.initials: A
authors.lastname: Habtezion
authors.affiliation: Applied Biomics, Hayward, CA 94545.
authors.forename: Jian
authors.initials: J
authors.lastname: Liao
authors.affiliation: Cell Biology/Biosciences, Faculty of Science and Engineering, Åbo Akademi University, Turku 20520, Finland.
authors.forename: M Nadeem
authors.initials: MN
authors.lastname: Asghar
authors.affiliation: Geriatric Research, Education and Clinical Center, VA Palo Alto Health Care System, and Stanford University School of Medicine, Palo Alto, CA 94304.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Geriatric Research, Education and Clinical Center, VA Palo Alto Health Care System, and Stanford University School of Medicine, Palo Alto, CA 94304.
authors.forename: Salman
authors.initials: S
authors.lastname: Azhar
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109 VA Ann Arbor Health Care System, Ann Arbor, MI 48105.
authors.forename: M Bishr
authors.initials: MB
authors.lastname: Omary
authors.affiliation: Cell Biology/Biosciences, Faculty of Science and Engineering, Åbo Akademi University, Turku 20520, Finland dtoivola@abo.fi.
authors.forename: Diana M
authors.initials: DM
authors.lastname: Toivola
mesh_terms: D000818:Animals; D003106:Colon / Q000166:cytology / Q000378:metabolism*; D015536:Down-Regulation; D004734:Energy Metabolism; D005260:Female; D017353:Gene Deletion; D006904:Hydroxymethylglutaryl-CoA Synthase / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism; D053533:Keratin-8 / Q000235:genetics*; D007657:Ketone Bodies / Q000096:biosynthesis*; D008297:Male; D051379:Mice; D027501:Monocarboxylic Acid Transporters / Q000235:genetics; D047493:PPAR alpha / Q000235:genetics; D027981:Symporters / Q000235:genetics; D000099233:Monocarboxylate Transport Protein 1
chemical_list: D006904:Hydroxymethylglutaryl-CoA Synthase; D053533:Keratin-8; D007657:Ketone Bodies; D027501:Monocarboxylic Acid Transporters; D047493:PPAR alpha; D027981:Symporters; D000099233:Monocarboxylate Transport Protein 1; C486595:Krt8 protein, mouse; C000607500:HMGCS2 protein, mouse