<i>R</i>-α-Lipoic Acid and 4-Phenylbutyric Acid Have Distinct Hypolipidemic Mechanisms in Hepatic Cells
The constitutive activation of the mechanistic target of rapamycin complex 1 (mTORC1) leads to the overproduction of apoB-containing triacylglycerol-rich lipoproteins in HepG2 cells. <i>R</i>-α-lipoic acid (LA) and 4-phenylbutyric acid (PBA) have hypolipidemic function but their mechanis...
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-08-01
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| Series: | Biomedicines |
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| Online Access: | https://www.mdpi.com/2227-9059/8/8/289 |
| _version_ | 1797557852939747328 |
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| author | Bo He Régis Moreau |
| author_facet | Bo He Régis Moreau |
| author_sort | Bo He |
| collection | DOAJ |
| description | The constitutive activation of the mechanistic target of rapamycin complex 1 (mTORC1) leads to the overproduction of apoB-containing triacylglycerol-rich lipoproteins in HepG2 cells. <i>R</i>-α-lipoic acid (LA) and 4-phenylbutyric acid (PBA) have hypolipidemic function but their mechanisms of action are not well understood. Here, we reported that LA and PBA regulate hepatocellular lipid metabolism via distinct mechanisms. The use of SQ22536, an inhibitor of adenylyl cyclase, revealed cAMP’s involvement in the upregulation of <i>CPT1A</i> expression by LA but not by PBA. LA decreased the secretion of proprotein convertase subtilisin/kexin type 9 (PCSK9) in the culture media of hepatic cells and increased the abundance of LDL receptor (LDLR) in cellular extracts in part through transcriptional upregulation. Although PBA induced <i>LDLR</i> gene expression, it did not translate into more LDLR proteins. PBA regulated cellular lipid homeostasis through the induction of <i>CPT1A</i> and <i>INSIG2</i> expression via an epigenetic mechanism involving the acetylation of histone H3, histone H4, and CBP-p300 at the <i>CPT1A</i> and <i>INSIG2</i> promoters. |
| first_indexed | 2024-03-10T17:22:09Z |
| format | Article |
| id | doaj.art-1b6c4ebfb94749ddbe509cf0d7ede752 |
| institution | Directory Open Access Journal |
| issn | 2227-9059 |
| language | English |
| last_indexed | 2024-03-10T17:22:09Z |
| publishDate | 2020-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomedicines |
| spelling | doaj.art-1b6c4ebfb94749ddbe509cf0d7ede7522023-11-20T10:17:12ZengMDPI AGBiomedicines2227-90592020-08-018828910.3390/biomedicines8080289<i>R</i>-α-Lipoic Acid and 4-Phenylbutyric Acid Have Distinct Hypolipidemic Mechanisms in Hepatic CellsBo He0Régis Moreau1Department of Nutrition and Health Sciences, University of Nebraska-Lincoln, Lincoln, NE 68583-0806, USADepartment of Nutrition and Health Sciences, University of Nebraska-Lincoln, Lincoln, NE 68583-0806, USAThe constitutive activation of the mechanistic target of rapamycin complex 1 (mTORC1) leads to the overproduction of apoB-containing triacylglycerol-rich lipoproteins in HepG2 cells. <i>R</i>-α-lipoic acid (LA) and 4-phenylbutyric acid (PBA) have hypolipidemic function but their mechanisms of action are not well understood. Here, we reported that LA and PBA regulate hepatocellular lipid metabolism via distinct mechanisms. The use of SQ22536, an inhibitor of adenylyl cyclase, revealed cAMP’s involvement in the upregulation of <i>CPT1A</i> expression by LA but not by PBA. LA decreased the secretion of proprotein convertase subtilisin/kexin type 9 (PCSK9) in the culture media of hepatic cells and increased the abundance of LDL receptor (LDLR) in cellular extracts in part through transcriptional upregulation. Although PBA induced <i>LDLR</i> gene expression, it did not translate into more LDLR proteins. PBA regulated cellular lipid homeostasis through the induction of <i>CPT1A</i> and <i>INSIG2</i> expression via an epigenetic mechanism involving the acetylation of histone H3, histone H4, and CBP-p300 at the <i>CPT1A</i> and <i>INSIG2</i> promoters.https://www.mdpi.com/2227-9059/8/8/289thioctic acidbutyratehyperlipidemiadyslipidemiatriacylglyceridescAMP |
| spellingShingle | Bo He Régis Moreau <i>R</i>-α-Lipoic Acid and 4-Phenylbutyric Acid Have Distinct Hypolipidemic Mechanisms in Hepatic Cells Biomedicines thioctic acid butyrate hyperlipidemia dyslipidemia triacylglycerides cAMP |
| title | <i>R</i>-α-Lipoic Acid and 4-Phenylbutyric Acid Have Distinct Hypolipidemic Mechanisms in Hepatic Cells |
| title_full | <i>R</i>-α-Lipoic Acid and 4-Phenylbutyric Acid Have Distinct Hypolipidemic Mechanisms in Hepatic Cells |
| title_fullStr | <i>R</i>-α-Lipoic Acid and 4-Phenylbutyric Acid Have Distinct Hypolipidemic Mechanisms in Hepatic Cells |
| title_full_unstemmed | <i>R</i>-α-Lipoic Acid and 4-Phenylbutyric Acid Have Distinct Hypolipidemic Mechanisms in Hepatic Cells |
| title_short | <i>R</i>-α-Lipoic Acid and 4-Phenylbutyric Acid Have Distinct Hypolipidemic Mechanisms in Hepatic Cells |
| title_sort | i r i α lipoic acid and 4 phenylbutyric acid have distinct hypolipidemic mechanisms in hepatic cells |
| topic | thioctic acid butyrate hyperlipidemia dyslipidemia triacylglycerides cAMP |
| url | https://www.mdpi.com/2227-9059/8/8/289 |
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