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Farnesoid X Receptor Activation by Obeticholic Acid Elevates Liver Low-Density Lipoprotein Receptor Expression by mRNA Stabilization and Reduces Plasma Low-Density Lipoprotein Cholesterol in Mice
Abstract
Objective—: The objective of this study was to determine whether and how activation of farnesoid X receptor (FXR) by obeticholic acid (OCA), a clinical FXR agonist, modulates liver low-density lipoprotein receptor (LDLR) expression under normolipidemic conditions. Approach and Results—: Administration of OCA to chow-fed mice increased mRNA and protein levels of LDLR in the liver without affecting the sterol-regulatory element binding protein pathway. Profiling of known LDLR mRNA-binding proteins demonstrated that OCA treatment did not affect expressions of mRNA degradation factors hnRNPD (heterogeneous nuclear ribonucleoprotein D) or ZFP36L1 but increased the expression of Hu antigen R (HuR) an mRNA-stabilizing factor. Furthermore, inducing effects of OCA on LDLR and HuR expression were ablated in Fxr −/− mice. To confirm the post-transcriptional mechanism, we used transgenic mice (albumin-luciferase-untranslated region) that express a human LDLR mRNA 3′ untranslated region luciferase reporter gene in the liver. OCA treatment led to significant rises in hepatic bioluminescence signals, Luc-untranslated region chimeric mRNA levels, and endogenous LDLR protein abundance, which were accompanied by elevations of hepatic HuR mRNA and protein levels in OCA-treated transgenic mice. In vitro studies conducted in human primary hepatocytes and HepG2 cells demonstrated that FXR activation by OCA and other agonists elicited the same inducing effect on LDLR expression as in the liver of normolipidemic mice. Furthermore, depletion of HuR in HepG2 cells by short interfering RNA transfection abolished the inducing effect of OCA on LDLR expression. Conclusions—: Our study is the first to demonstrate that FXR activation increases LDLR expression in liver tissue by a post-transcriptional regulatory mechanism involving LDLR mRNA-stabilizing factor HuR.
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HuR/ELAVL1 binds the same AREs to stabilize LDLR mRNA and increase LDLR proteins in hepatocytes.
“While these RBPs destabilize their mRNA targets leading to degradation of LDLR, human antigen R (HuR), also known as ELAV-like RNA binding protein 1 (ELAVL1), binds the same AREs to stabilize LDLR mRNA and increase LDLR proteins in hepatocytes65,66.”
From Pathways and Molecular Mechanisms Governing LDL Receptor Regulation (2025) · cites this paper as [65]
HuR confers stability to LDLR mRNA.
“Among these, Hu antigen R (HuR) is one of the few RBPs identified that confers stability to LDLR mRNA [9,13,14]”
From Triciribine Engages ZFP36L1 and HuR to Stabilize LDLR mRNA (2020) · cites this paper as [9]
HuR and ZFP36L1 were considered likely candidates because they have been reported to modulate LDLR mRNA stability in response to agents that activate ERK and their mechanisms have been partially resolved.
“These two proteins were considered to be likely candidates, because (1) they have been reported to modulate LDLR mRNA stability in response to agents that activate ERK and (2) the mechanisms underlying their regulatory effect on LDLR mRNA stability have been partially resolved [9,13,14,15].”
From Triciribine Engages ZFP36L1 and HuR to Stabilize LDLR mRNA (2020) · cites this paper as [9]
LDLR mRNA is stabilized in an HuR-dependent manner in response to farnesoid X receptor activation and the AMPK activator AICAR.
“One such target is LDLR mRNA [13], which is stabilized in an HuR-dependent manner in response to farnesoid X receptor activation and the AMPK activator, AICAR [9,14].”
From Triciribine Engages ZFP36L1 and HuR to Stabilize LDLR mRNA (2020) · cites this paper as [9]
LDLR mRNA becomes stabilized two- to three-fold in response to extracellular stimuli including PMA, bile acids, berberine, and TCN.
“LDLR mRNA has a half-life of approximately 1–2 h in HepG2 cells and it becomes stabilized two- to three-fold in response to extracellular stimuli, including phorbol 12-myristate 13-acetate (PMA) [7], bile acids [8,9], berberine (BBR) [5,10,11], and triciribine (TCN) [12].”
From Triciribine Engages ZFP36L1 and HuR to Stabilize LDLR mRNA (2020) · cites this paper as [9]
ZFP36L1 is a LDLR mRNA-destabilizing protein in HepG2 cells.
“confirms ZFP36L1 as a LDLR mRNA-destabilizing protein in HepG2 cells [9,13,14,15]”
From Triciribine Engages ZFP36L1 and HuR to Stabilize LDLR mRNA (2020) · cites this paper as [9]
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Pathways and Molecular Mechanisms Governing LDL Receptor Regulation
Schmidt, H. M., Jarrett, K. E., de Aguiar Vallim, T. Q., & Tarling, E. J. (2025) · Circulation Research · doi:10.1161/circresaha.124.323578 · Cited by 33
RNA-binding proteins in vascular inflammation and atherosclerosis
Sachse, M., Tual-Chalot, S., Ciliberti, G., Amponsah-Offeh, M., Stamatelopoulos, K., Gatsiou, A., & Stellos, K. (2023) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2023.01.008 · Cited by 29
Triciribine Engages ZFP36L1 and HuR to Stabilize LDLR mRNA
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Metadata
- Authors
- Singh, A. B., Dong, B., Kraemer, F. B., Xu, Y., Zhang, Y., & Liu, J.
- Affiliations
- From the Veterans Affairs Palo Alto Health Care System, CA (A.B.S., B.D., F.B.K., J.L.)
- Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown (Y.X., Y.Z.).
- Venue
- Arteriosclerosis, Thrombosis, and Vascular Biology
- Published
- 2018-10
- Volume
- 38
- Issue
- 10
- Pages
- 2448-2459
- ISSN
- 1079-5642
- 1524-4636
- PMC
- PMC6206879
- Cited by
- 31
- References
- 7
- Language
- en
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