Identification of miR-185 as a regulator of de novo cholesterol biosynthesis and low density lipoprotein uptake

Yang, Muhua; Liu, Weidong; Pellicane, Christina; Sahyoun, Christine; Joseph, Biny K.; Gallo-Ebert, Christina; Donigan, Melissa; Pandya, Devanshi; Giordano, Caroline; Bata, A; Nickels, Joseph T.

doi:10.1194/jlr.m041335

Cited by 90 publications

(84 citation statements)

References 83 publications

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“…Thus, one possible explanation for the increased HMGCR expression in Dicer1-KO mouse livers may be due to some miRNAs deficiency, which prevented the targeting of HMGCR. Recent studies have shown that some miRNAs can downregulate the expression of HMGCR directly or indirectly [24,26,[46][47][48] . For example, miR-21 can regulate cholesterol metabolism by targeting HMGCR directly in vitro [46] .…”

Section: Discussionmentioning

confidence: 99%

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Dicer1/miR-29/HMGCR axis contributes to hepatic free cholesterol accumulation in mouse non-alcoholic steatohepatitis

et al. 2017

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Dicer1 is an enzyme essential for microRNA (miRNA) maturation. The loss of miRNAs resulted from Dicer1 deficiency greatly contributes to the progression of many diseases, including lipid dysregulation, but its role in hepatic accumulation of free cholesterol (FC) that is critical in the development of non-alcoholic steatohepatitis (NASH) remains elusive. In this study, we used the liver-specific Dicer1-knockout mice to identify the miRNAs involved in hepatic FC accumulation. In a widely used dietary NASH model, mice were fed a methionine-choline-deficient (MCD) diet for 3 weeks, which resulted in significant increase in hepatic FC levels as well as decrease of Dicer1 mRNA levels in livers. The liver-specific Dicer1-knockout induced hepatic FC accumulation at 5-6 weeks, accompanied by increased mRNA and protein levels of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), a rate-limiting enzyme of cholesterol synthesis in livers. Eleven predicted miRNAs were screened, revealing that miR-29a/b/c significantly suppressed HMGCR expression by targeting the HMGCR mRNA 3'-UTR. Overexpression of miR-29a in SMMC-7721 cells, a steatosis hepatic cell model, significantly decreased HMGCR expression and the FC level. Furthermore, the expression levels of miR-29a were inversely correlated with HMGCR expression levels in the MCD diet mouse model in vivo and in 2 steatosis hepatic cell models (SMMC-7721 and HL-7702 cells) in vitro. Our results show that Dicer1/miR-29/HMGCR axis contributes to hepatic free cholesterol accumulation in mouse NASH, and miR-29 may serve as an important regulator of hepatic cholesterol homeostasis. Thus, miR-29a could be utilized as a potential therapeutic target for the treatment of non-alcoholic fatty liver disease as well as for other liver diseases associated with FC accumulation.

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Section: Discussionmentioning

confidence: 99%

“…For example, miR-21 can regulate cholesterol metabolism by targeting HMGCR directly in vitro [46] . [48] . Indeed, here, we identified miR-29a/b/c to be affected by Dicer1-deficiency; thus, their inhibitory effect on HMGCR mRNA and protein expression (Figure 4) was diminished by Dicer1 knockout.…”

Section: Discussionmentioning

confidence: 99%

Dicer1/miR-29/HMGCR axis contributes to hepatic free cholesterol accumulation in mouse non-alcoholic steatohepatitis

et al. 2017

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“…Yang et al (2014) evidenced that mice with elevated cholesterol had levels of miR-185 expression five times higher than the control group. Induced inhibition of miR-185 caused decreased expression of the SREBP-2, LDLR and PCSK9 genes and HMG-CoA reductase activity.…”

Section: Mir-185mentioning

confidence: 98%

“…Recently, several miRNAs have been implicated in the regulation of lipid metabolism [37][38]. Several studies have shown that modulation of specific miRNAs can directly influence lipid metabolism through post-transcriptional control of key genes such as LDLR.…”

Section: Role Of Mirnas In the Regulation Of Pcsk9 And Ldlrmentioning

confidence: 99%

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Profile of Surrounding MicroRNAs in Low Density Lipoprotein Uptake

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et al. 2017

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Abstract:The atherosclerosis, a chronic and inflammatory disease that occurs when there are high levels of low-density lipoprotein (LDL) on plasma. This important risk factor for development of cardiovascular disease (CVD) is the main cause of death worldwide. MicroRNAs have recently emerged as potential biomarkers and therapeutic target for lipid metabolism disorders. In this review, we will provide profile of surrounding miRNAs that have demonstrated being regulators of PCSK9, LDLR and APOB100 genes. Recent work has identified the mir-148, mir-128, mir-27a/b, mir-185, mir-301, mir-130 as important regulators of this pathway because they decrease supply of LDL receptors through interaction with PCSK9. Inhibition of LDLR expression cause elevation of plasma LDL levels which induces atherosclerosis. While mir-30c, mir-122, mir-34 decrease MTTP, which promotes degradation of APOB100 preventing assembly and secretion of VLDL. We conclude that, when overexpressed, mir-148a, mir128 and mir-27a/b, mir-122 and mir-34 are related to decrease in LDLR, facilitating occurrence of atherosclerosis. While mir-30 has been linked to decreased atherosclerosis. Detection of miRNAs profile could be used in the future as a biomarker for disturbs linked to c-LDL uptake and in future anti-miRNAs therapies may be used in the treatment of atherosclerosis.

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