Identification of novel regulatory cholesterol metabolite, 5-cholesten, 3β,25-diol, disulfate.
Oxysterol sulfation plays an important role in regulation of lipid metabolism and inflammatory responses. In the present study, we report the discovery of a novel regulatory sulfated oxysterol in nuclei of primary rat hepatocytes after overexpression of the gene encoding mitochondrial cholesterol de...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2014-01-01
|
| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC4114806?pdf=render |
| _version_ | 1828264110883602432 |
|---|---|
| author | Shunlin Ren Jin Koung Kim Genta Kakiyama Daniel Rodriguez-Agudo William M Pandak Hae-Ki Min Yanxia Ning |
| author_facet | Shunlin Ren Jin Koung Kim Genta Kakiyama Daniel Rodriguez-Agudo William M Pandak Hae-Ki Min Yanxia Ning |
| author_sort | Shunlin Ren |
| collection | DOAJ |
| description | Oxysterol sulfation plays an important role in regulation of lipid metabolism and inflammatory responses. In the present study, we report the discovery of a novel regulatory sulfated oxysterol in nuclei of primary rat hepatocytes after overexpression of the gene encoding mitochondrial cholesterol delivery protein (StarD1). Forty-eight hours after infection of the hepatocytes with recombinant StarD1 adenovirus, a water-soluble oxysterol product was isolated and purified by chemical extraction and reverse-phase HPLC. Tandem mass spectrometry analysis identified the oxysterol as 5-cholesten-3β, 25-diol, disulfate (25HCDS), and confirmed the structure by comparing with a chemically synthesized compound. Administration of 25HCDS to human THP-1-derived macrophages or HepG2 cells significantly inhibited cholesterol synthesis and markedly decreased lipid levels in vivo in NAFLD mouse models. RT-PCR showed that 25HCDS significantly decreased SREBP-1/2 activities by suppressing expression of their responding genes, including ACC, FAS, and HMG-CoA reductase. Analysis of lipid profiles in the liver tissues showed that administration of 25HCDS significantly decreased cholesterol, free fatty acids, and triglycerides by 30, 25, and 20%, respectively. The results suggest that 25HCDS inhibits lipid biosynthesis via blocking SREBP signaling. We conclude that 25HCDS is a potent regulator of lipid metabolism and propose its biosynthetic pathway. |
| first_indexed | 2024-04-13T04:19:55Z |
| format | Article |
| id | doaj.art-e8250311858644149af3890f2efe236f |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-04-13T04:19:55Z |
| publishDate | 2014-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-e8250311858644149af3890f2efe236f2022-12-22T03:02:49ZengPublic Library of Science (PLoS)PLoS ONE1932-62032014-01-0197e10362110.1371/journal.pone.0103621Identification of novel regulatory cholesterol metabolite, 5-cholesten, 3β,25-diol, disulfate.Shunlin RenJin Koung KimGenta KakiyamaDaniel Rodriguez-AgudoWilliam M PandakHae-Ki MinYanxia NingOxysterol sulfation plays an important role in regulation of lipid metabolism and inflammatory responses. In the present study, we report the discovery of a novel regulatory sulfated oxysterol in nuclei of primary rat hepatocytes after overexpression of the gene encoding mitochondrial cholesterol delivery protein (StarD1). Forty-eight hours after infection of the hepatocytes with recombinant StarD1 adenovirus, a water-soluble oxysterol product was isolated and purified by chemical extraction and reverse-phase HPLC. Tandem mass spectrometry analysis identified the oxysterol as 5-cholesten-3β, 25-diol, disulfate (25HCDS), and confirmed the structure by comparing with a chemically synthesized compound. Administration of 25HCDS to human THP-1-derived macrophages or HepG2 cells significantly inhibited cholesterol synthesis and markedly decreased lipid levels in vivo in NAFLD mouse models. RT-PCR showed that 25HCDS significantly decreased SREBP-1/2 activities by suppressing expression of their responding genes, including ACC, FAS, and HMG-CoA reductase. Analysis of lipid profiles in the liver tissues showed that administration of 25HCDS significantly decreased cholesterol, free fatty acids, and triglycerides by 30, 25, and 20%, respectively. The results suggest that 25HCDS inhibits lipid biosynthesis via blocking SREBP signaling. We conclude that 25HCDS is a potent regulator of lipid metabolism and propose its biosynthetic pathway.http://europepmc.org/articles/PMC4114806?pdf=render |
| spellingShingle | Shunlin Ren Jin Koung Kim Genta Kakiyama Daniel Rodriguez-Agudo William M Pandak Hae-Ki Min Yanxia Ning Identification of novel regulatory cholesterol metabolite, 5-cholesten, 3β,25-diol, disulfate. PLoS ONE |
| title | Identification of novel regulatory cholesterol metabolite, 5-cholesten, 3β,25-diol, disulfate. |
| title_full | Identification of novel regulatory cholesterol metabolite, 5-cholesten, 3β,25-diol, disulfate. |
| title_fullStr | Identification of novel regulatory cholesterol metabolite, 5-cholesten, 3β,25-diol, disulfate. |
| title_full_unstemmed | Identification of novel regulatory cholesterol metabolite, 5-cholesten, 3β,25-diol, disulfate. |
| title_short | Identification of novel regulatory cholesterol metabolite, 5-cholesten, 3β,25-diol, disulfate. |
| title_sort | identification of novel regulatory cholesterol metabolite 5 cholesten 3β 25 diol disulfate |
| url | http://europepmc.org/articles/PMC4114806?pdf=render |
| work_keys_str_mv | AT shunlinren identificationofnovelregulatorycholesterolmetabolite5cholesten3b25dioldisulfate AT jinkoungkim identificationofnovelregulatorycholesterolmetabolite5cholesten3b25dioldisulfate AT gentakakiyama identificationofnovelregulatorycholesterolmetabolite5cholesten3b25dioldisulfate AT danielrodriguezagudo identificationofnovelregulatorycholesterolmetabolite5cholesten3b25dioldisulfate AT williammpandak identificationofnovelregulatorycholesterolmetabolite5cholesten3b25dioldisulfate AT haekimin identificationofnovelregulatorycholesterolmetabolite5cholesten3b25dioldisulfate AT yanxianing identificationofnovelregulatorycholesterolmetabolite5cholesten3b25dioldisulfate |