A novel posttranscriptional mechanism for dietary cholesterol-mediated suppression of liver LDL receptor expression

Abstract

The expression of liver LDL receptor (LDLR) regulates human plasma LDL-cholesterol (LDL-C) homeostasis ( 1-3 ). Increased hepatic LDLR expression results in improved clearance of plasma LDL-C through receptor-mediated endocytosis, which is strongly associated with a decreased risk of developing cardiovascular disease in humans ( 4, 5 ). Thus far, many studies have demonstrated that intracellular cholesterol levels play a primary role in determination of hepatic LDLR expression levels through a negative feedback mechanism that controls gene transcription mediated by the sterolregulatory element (SRE) located in LDLR promoter and SRE binding proteins (SREBPs) ( 6, 7 ).In addition to transcriptional regulation, LDLR gene expression is subject to posttranscriptional regulation at the point of mRNA stability ( 8-11 ). It is well-known that mRNA stability plays a key role in the control of gene expression both by setting the basal level of gene expression and as a site of regulatory responses ( 12 ). In liver cells, when intracellular cholesterol levels rise, LDLR mRNA levels fall substantially along with transcripts of other SREBP target genes ( 13 ). While this decrease in LDLR mRNA abundance has been attributed to the transcriptional suppression due to the inhibition of proteolytic processing of SREBP ( 14, 15 ), it is currently unknown whether elevated cholesterol levels can also elicit a cellular response to increase LDLR mRNA turnover rate as a rapid means to

Reduction of circulating PCSK9 and LDL-C levels by liver-specific knockdown of HNF1α in normolipidemic mice

“…However, signifi cant reductions in hepatic PCSK9 mRNA expression and serum PCSK9 concentrations were only observed in the Ad-shHNF1 ␣ virusinfected animals. Of note is that the infection dose of 4-6 × 10 9 PFU/animal and timeline (7-10 days postinfection) of analysis is consistent with other reports using adenoviral delivery vectors to knockdown gene expression in murine livers (33)(34)(35). Consistent with in vitro results, in vivo knockdown of HNF1 ␤ did not result in repression of hepatic PCSK9 mRNA levels.…”

Inhibition of PCSK9 Transcription by Berberine Involves Down-regulation of Hepatic HNF1α Protein Expression through the Ubiquitin-Proteasome Degradation Pathway

“…As we expected, whereas HNF1␣ mRNA levels were barely changed by any of the treatments, PCSK9 mRNA expression levels were reduced by BBR and increased by BTZ without or with BBR, which was consistent with the results of Western blot analysis. It is worthy to note that our previous studies have demonstrated that BBR increases LDLR mRNA levels by mRNA stabilization mediated through the LDLR mRNA 3Ј-untranslated region (17,20), and this BBR effect was not affected by the proteasome inhibitor. BTZ treatment did not alter LDLR mRNA levels in uninduced control cells or in BBR-stimulated cells.…”

“…Animal Diet and BBR Treatment-2-3-month-old FVB mice expressing a luciferase reporter gene (20) were used in the BBR study. The expression of the luciferase in these mice is irrelevant to this study.…”

Empagliflozin, via Switching Metabolism Toward Lipid Utilization, Moderately Increases LDL Cholesterol Levels Through Reduced LDL Catabolism

“…The increased hepatic fatty acids levels may fuel the pool of acetyl-CoA, an important metabolic branch point, as a source for both ketone body production and hepatic cholesterol synthesis (13), with the latter associated with higher HMG-CoA reductase activity and hepatic total cholesterol levels. As hepatic levels of cholesterol regulate LDL receptor expression (14,15), empagliflozin treatment lowered LDL receptor expression and plasma LDL-C catabolism, which in turn increased LDL-C plasma levels. Although a raise in LDL-C levels is seen as an increase in cardiovascular event risk (16), it is probably not so prominent with empagliflozin.…”