title: SREBP2 Activation Induces Hepatic Long-chain Acyl-CoA Synthetase 1 (ACSL1) Expression in Vivo and in Vitro through a Sterol Regulatory Element (SRE) Motif of the ACSL1 C-promoter.
abstract: Long-chain acyl-CoA synthetase 1 (ACSL1) plays a key role in fatty acid metabolism. To identify novel transcriptional modulators of ACSL1, we examined ACSL1 expression in liver tissues of hamsters fed a normal diet, a high fat diet, or a high cholesterol and high fat diet (HCHFD). Feeding hamsters HCHFD markedly reduced hepatic Acsl1 mRNA and protein levels as well as acyl-CoA synthetase activity. Decreases in Acsl1 expression strongly correlated with reductions in hepatic Srebp2 mRNA level and mature Srebp2 protein abundance. Conversely, administration of rosuvastatin (RSV) to hamsters increased hepatic Acsl1 expression. These new findings were reproduced in mice treated with RSV or fed the HCHFD. Furthermore, the RSV induction of acyl-CoA activity in mouse liver resulted in increases in plasma and hepatic cholesterol ester concentrations and reductions in free cholesterol amounts. Investigations on different ACSL1 transcript variants in HepG2 cells revealed that the mRNA expression of C-ACSL1 was specifically regulated by the sterol regulatory element (SRE)-binding protein (SREBP) pathway, and RSV treatment increased the C-ACSL1 abundance from a minor mRNA species to an abundant transcript. We analyzed 5'-flanking sequence of exon 1C of the human ACSL1 gene and identified one putative SRE site. By performing a promoter activity assay and DNA binding assays, we firmly demonstrated the key role of this SRE motif in SREBP2-mediated activation of C-ACSL1 gene transcription. Finally, we demonstrated that knockdown of endogenous SREBP2 in HepG2 cells lowered ACSL1 mRNA and protein levels. Altogether, this work discovered an unprecedented link between ACSL1 and SREBP2 via the specific regulation of the C-ACSL1 transcript.
authors.affiliation: From the Department of Veterans Affairs Palo Alto Health Care System, Palo Alto, California 94304.
authors.forename: Amar Bahadur
authors.initials: AB
authors.lastname: Singh
authors.affiliation: From the Department of Veterans Affairs Palo Alto Health Care System, Palo Alto, California 94304.
authors.forename: Chin Fung Kelvin
authors.initials: CF
authors.lastname: Kan
authors.affiliation: From the Department of Veterans Affairs Palo Alto Health Care System, Palo Alto, California 94304.
authors.forename: Bin
authors.initials: B
authors.lastname: Dong
authors.affiliation: From the Department of Veterans Affairs Palo Alto Health Care System, Palo Alto, California 94304 Jingwen.Liu@va.gov.
authors.forename: Jingwen
authors.initials: J
authors.lastname: Liu
mesh_terms: D000818:Animals; D001665:Binding Sites; D002784:Cholesterol / Q000097:blood / Q000378:metabolism; D003066:Coenzyme A Ligases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006224:Cricetinae; D059305:Diet, High-Fat; D056945:Hep G2 Cells; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008647:Mesocricetus; D051379:Mice; D008810:Mice, Inbred C57BL; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020218:Response Elements; D051782:Sterol Regulatory Element Binding Protein 2 / Q000378:metabolism*
chemical_list: D012333:RNA, Messenger; D051782:Sterol Regulatory Element Binding Protein 2; D002784:Cholesterol; D003066:Coenzyme A Ligases; C583414:ACSL1 protein, human
keywords: ACSL1; SREBP; acyl-CoA synthetase; dietary cholesterol; fatty acid metabolism; lipid metabolism; liver; statin; transcription promoter; transcription regulation