Hepatic Cholesterol-25-Hydroxylase Overexpression Improves Systemic Insulin Sensitivity in Mice.

Publisher: Hindawi Limited Country of Publication: England NLM ID: 101605237 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2314-6753 (Electronic) NLM ISO Abbreviation: J Diabetes Res Subsets: MEDLINE

Publication: <2019>-: London, United Kingdom : Hindawi Limited
Original Publication: Nasr City, Cairo : Hindawi Publishing Corporation, [2013]-

Diabetes Mellitus, Type 2/*genetics ; Insulin Resistance/*genetics ; Liver/*metabolism ; Obesity/*genetics ; Steroid Hydroxylases/*genetics; Animals ; Blood Glucose/metabolism ; Diabetes Mellitus, Type 2/metabolism ; Disease Progression ; Male ; Mice ; Mice, Transgenic ; Obesity/metabolism ; Steroid Hydroxylases/metabolism

Obesity is a major risk factor for several diseases including diabetes, heart disease, and some forms of cancer and due to its rapidly increasing prevalence it has become one of the biggest problems medicine is facing today. All the more surprising, a substantial percentage of obese patients are metabolically healthy when classified based on insulin resistance and systemic inflammation. Oxysterols are naturally occurring molecules that play important role in various metabolic and inflammatory processes and their levels are elevated in patients suffering from obesity and diabetes. 25-Hydroxycholesterol (25-OHC) is produced in cells from cholesterol by the enzyme cholesterol 25-hydroxylase (Ch25h) and is involved in lipid metabolism, inflammatory processes, and cell proliferation. Here, we investigated the role of hepatic Ch25h in the transition from metabolically healthy obesity to insulin resistance and diabetes. Using several different experimental approaches, we demonstrated the significance of Ch25h on the border of "healthy" and "diseased" states of obesity. Adenovirus-mediated Ch25h overexpression in mice improved glucose tolerance and insulin sensitivity and lowered HOMA-IR. Our data suggest that low hepatic Ch25h levels could be considered a risk marker for unhealthy obesity.
Competing Interests: The authors declare no conflict of interests associated with this manuscript.

Cytokine. 2008 Oct;44(1):141-8. (PMID: 18723371)
J Lipid Res. 2009 Nov;50(11):2258-64. (PMID: 19502589)
J Lipid Res. 2003 Sep;44(9):1780-9. (PMID: 12810827)
Endocr Rev. 2008 Dec;29(7):939-60. (PMID: 18723451)
Mol Endocrinol. 2003 Jun;17(6):985-93. (PMID: 12690094)
Biochimie. 2013 Mar;95(3):455-60. (PMID: 22732193)
J Virol. 1997 Mar;71(3):1842-9. (PMID: 9032314)
Curr Opin Genet Dev. 1998 Oct;8(5):571-5. (PMID: 9794827)
J Biol Chem. 1998 Dec 18;273(51):34316-27. (PMID: 9852097)
Neurosci Lett. 2004 Sep 30;368(3):303-8. (PMID: 15364416)
Ann Med. 2004;36(8):562-72. (PMID: 15768828)
PLoS One. 2016 Jan 26;11(1):e0147179. (PMID: 26812621)
Biochim Biophys Acta. 2000 Dec 15;1529(1-3):126-35. (PMID: 11111082)
Proc Natl Acad Sci U S A. 2009 Sep 8;106(36):15430-5. (PMID: 19706383)
3 Biotech. 2011 Sep;1(2):99-109. (PMID: 22582164)
Neurosci Lett. 2002 Oct 18;331(3):163-6. (PMID: 12383922)
J Clin Endocrinol Metab. 2008 Nov;93(11):4282-9. (PMID: 18713821)
Clin Chim Acta. 2012 Aug 16;413(15-16):1163-70. (PMID: 22521751)
Lancet Neurol. 2005 Dec;4(12):841-52. (PMID: 16297842)
WMJ. 1998 Oct;97(9):20-1, 24-5, 27-37. (PMID: 9810255)
Nat Immunol. 2011 May;12(5):408-15. (PMID: 21478880)
Lancet Diabetes Endocrinol. 2013 Oct;1(2):152-62. (PMID: 24622321)
J Lipid Res. 2009 Jul;50(7):1374-83. (PMID: 19287042)
Proc Natl Acad Sci U S A. 2009 Sep 29;106(39):16764-9. (PMID: 19805370)
Am J Physiol Endocrinol Metab. 2014 Jan 15;306(2):E123-30. (PMID: 24302009)
Gastroenterology. 2013 Jan;144(1):167-178.e1. (PMID: 23041327)
Cell Metab. 2013 May 7;17(5):644-656. (PMID: 23583168)
Proc Natl Acad Sci U S A. 2014 Jul 22;111(29):10666-71. (PMID: 24994901)
Neurobiol Dis. 2013 Jul;55:37-43. (PMID: 23557875)
Eur J Clin Invest. 2002 Jan;32(1):35-42. (PMID: 11851725)
Diabetes. 2011 Jun;60(6):1668-76. (PMID: 21536945)
Neurosci Lett. 2009 Oct 2;462(1):89-93. (PMID: 19560513)
Cell Metab. 2007 Jan;5(1):73-9. (PMID: 17189208)
Nat Immunol. 2010 Feb;11(2):136-40. (PMID: 20023662)
Sci Rep. 2016 Jan 22;6:19694. (PMID: 26795945)
Annu Rev Physiol. 2010;72:219-46. (PMID: 20148674)
J Clin Invest. 2000 Jul;106(2):171-6. (PMID: 10903330)
Respir Res. 2012 Jul 31;13:63. (PMID: 22849850)
Cell. 2014 Jul 3;158(1):25-40. (PMID: 24995976)
Neuroreport. 2000 Jun 26;11(9):1959-62. (PMID: 10884051)
Cell Metab. 2010 Sep 8;12(3):237-49. (PMID: 20816090)
Arterioscler Thromb Vasc Biol. 1999 Apr;19(4):967-71. (PMID: 10195924)
J R Soc Med. 2002;95 Suppl 42:8-13. (PMID: 12216329)
Curr Opin Pharmacol. 2012 Dec;12(6):729-35. (PMID: 22832233)
Mol Aspects Med. 2009 Jun;30(3):134-52. (PMID: 19248804)
Genes Dev. 2000 Nov 15;14(22):2819-30. (PMID: 11090130)
Science. 2014 Aug 8;345(6197):679-84. (PMID: 25104388)
Endocr Rev. 2000 Dec;21(6):697-738. (PMID: 11133069)
Cell. 2012 Mar 2;148(5):852-71. (PMID: 22385956)
Cell. 2007 Nov 2;131(3):476-91. (PMID: 17981116)
Nat Immunol. 2013 Sep;14(9):893-900. (PMID: 23959186)
Trends Pharmacol Sci. 2012 Jul;33(7):394-404. (PMID: 22541735)
Nat Immunol. 2011 May;12(5):379-80. (PMID: 21502990)
Genes Dev. 2000 Nov 15;14(22):2831-8. (PMID: 11090131)
Atherosclerosis. 2001 Sep;158(1):61-71. (PMID: 11500175)
Nat Rev Immunol. 2014 Nov;14(11):731-43. (PMID: 25324126)
Cell Metab. 2012 May 2;15(5):570-3. (PMID: 22560209)
Am J Physiol Endocrinol Metab. 2007 Dec;293(6):E1663-9. (PMID: 17911339)

0 (Blood Glucose)
EC 1.14.- (Steroid Hydroxylases)
EC 1.14.99.38 (cholesterol 25-hydroxylase)

Date Created: 20170317 Date Completed: 20170615 Latest Revision: 20240524

20240524

PMC5337352

10.1155/2017/4108768

28299341