miR-3666 inhibits development of hepatic steatosis by negatively regulating PPARγ

Mittal, Smriti; Inamdar, Shrirang; Acharya, Jhankar; Pekhale, Komal; Kalamkar, Saurabh; Boppana, Ramanamurthy; Ghaskadbi, Surendra

doi:10.1016/j.bbalip.2020.158777

Cited by 7 publications

(3 citation statements)

References 33 publications

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“…In addition, miR-3666, whose expression increased via EGCG treatment in the present study, was reported to suppress hepatic steatosis by targeting PPARγ (38). A previous study reported that EGCG suppresses nonalcoholic fatty liver disease (39).…”

Section: Discussionsupporting

confidence: 64%

(−)‑Epigallocatechin‑3‑O‑gallate upregulates the expression levels of miR‑6757‑3p, a suppressor of fibrosis‑related gene expression, in extracellular vesicles derived from human umbilical vein endothelial cells

et al. 2023

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As pulmonary fibrosis (PF), a severe interstitial pulmonary disease, has such a poor prognosis, the development of prevention and treatment methods is imperative. (−)-Epigallocatechin-3-O-gallate (EGCG), one of the major catechins in green tea, exerts an antifibrotic effect, although its mechanism remains unclear. Recently, it has been reported that microRNAs (miRNAs or miRs) transported by extracellular vesicles (EVs) from vascular endothelial cells (VECs) are involved in PF. In the present study, the effects of EGCG on the expression of miRNAs in EVs derived from human umbilical vein endothelial cells (HUVECs) were assessed and miRNAs with antifibrotic activity were identified. miRNA microarray analysis revealed that EGCG modulated the expression levels of 31 miRNAs (a total of 27 miRNAs were upregulated, and 4 miRNAs were downregulated.) in EVs from HUVECs. Furthermore, TargetScan analysis indicated that miR-6757-3p in particular, which exhibited the highest degree of change, may target transforming growth factor-β (TGF-β) receptor 1 (TGFBR1). To evaluate the effects of miR-6757-3p on TGFBR1 expression, human fetal lung fibroblasts (HFL-1) were transfected with an miR-6757-3p mimic. The results demonstrated that the miR-6757-3p mimic downregulated the expression of TGFBR1 as well the expression levels of fibrosis-related genes including fibronectin and α-smooth muscle actin in TGF-β-treated HFL-1 cells. In summary, EGCG upregulated the expression levels of miR-6757-3p, which may target TGFBR1 and downregulate fibrosis-related genes, in EVs derived from VECs.

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Section: Discussionsupporting

confidence: 64%

(−)‑Epigallocatechin‑3‑O‑gallate upregulates the expression levels of miR‑6757‑3p, a suppressor of fibrosis‑related gene expression, in extracellular vesicles derived from human umbilical vein endothelial cells

et al. 2023

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“…More interesting, several miRNAs have been identified as key regulators of hepatic steatosis. miR-30a-3p and miR-3666, for example, protect hepatocytes from steatosis by targeting PPARα and PPARγ, respectively [ 133 , 134 ]. Last but not least, the studies reviewed here and compiled in Table 3 affirm the relevance and complexity of the regulation of the miRNAs/PPARγ network in NAFLD emphasizing the necessity of continuing research in this promising field.…”

Section: The Role Of Epigenetic Mechanisms In Regulating Pparγ Regula...mentioning

confidence: 99%

Peroxisome Proliferator-Activated Receptor-γ as a Target and Regulator of Epigenetic Mechanisms in Nonalcoholic Fatty Liver Disease

Zaiou

2023

Cells

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Peroxisome proliferator-activated receptor-γ (PPARγ) belongs to the superfamily of nuclear receptors that control the transcription of multiple genes. Although it is found in many cells and tissues, PPARγ is mostly expressed in the liver and adipose tissue. Preclinical and clinical studies show that PPARγ targets several genes implicated in various forms of chronic liver disease, including nonalcoholic fatty liver disease (NAFLD). Clinical trials are currently underway to investigate the beneficial effects of PPARγ agonists on NAFLD/nonalcoholic steatohepatitis. Understanding PPARγ regulators may therefore aid in unraveling the mechanisms governing the development and progression of NAFLD. Recent advances in high-throughput biology and genome sequencing have greatly facilitated the identification of epigenetic modifiers, including DNA methylation, histone modifiers, and non-coding RNAs as key factors that regulate PPARγ in NAFLD. In contrast, little is still known about the particular molecular mechanisms underlying the intricate relationships between these events. The paper that follows outlines our current understanding of the crosstalk between PPARγ and epigenetic regulators in NAFLD. Advances in this field are likely to aid in the development of early noninvasive diagnostics and future NAFLD treatment strategies based on PPARγ epigenetic circuit modification.

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“…Various miRNAs have been recognized as key regulators of hepatic steatosis based on their complementation to the 3′ untranslated region (3’ UTR) of target mRNAs ( Bartel, 2009 ). For example, miR-30a-3p and miR-3666 protect hepatocytes from steatosis by targeting peroxisome proliferator-activated receptor (PPAR)-α and PPAR- γ , respectively ( Wang et al, 2020a ; Mittal et al, 2020 ). miR-29a ( Mattis et al, 2015 ), miR-185 ( Wang et al, 2014 ), and miR-192-3p ( Wang et al, 2020b ) also downregulate the expression of lipogenic genes, including those encoding the glucocorticoid receptor, FASN, 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), and SREBP-1c/2, to inhibit hepatic lipogenesis.…”

Section: Introductionmentioning

confidence: 99%

Profile analysis and functional modeling identify circular RNAs in nonalcoholic fatty liver disease as regulators of hepatic lipid metabolism

et al. 2022

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Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease, associated with an outcome of hepatic fibrosis/cirrhosis and hepatocellular carcinoma. However, limited exploration of the underlying mechanisms hinders its prevention and treatment. To investigate the mechanisms of epigenetic regulation in NAFLD, the expression profile of circular RNA (circRNA) of rodents in which NAFLD was induced by a high-fat, high-cholesterol (HFHC) diet was studied. Modeling of the circRNA-microRNA (miRNA) -mRNA regulatory network revealed the functional characteristics of NAFLD-specific circRNAs. The targets and effects in the liver of such NAFLD-specific circRNAs were further assessed. Our results uncovered that the downregulation of 28 annotated circRNAs characterizes HFHC diet-induced NAFLD. Among the downregulated circRNAs, long intergenic non-protein coding RNA, P53 induced transcript (LNCPINT) -derived circRNAs (circ_0001452, circ_0001453, and circ_0001454) targeted both miR-466i-3p and miR-669c-3p. Their deficiency in NAFLD abrogated the circRNA-based inhibitory effect on both miRNAs, which further inactivated the AMPK signaling pathway via AMPK-α1 suppression. Inhibition of the AMPK signaling pathway promotes hepatic steatosis, depending on the transcriptional and translational upregulation of lipogenic genes, such as those encoding sterol regulatory element-binding protein 1 (SREBP1) and fatty acid synthase (FASN) in hepatocytes. The levels of LNCPINT-derived circRNAs displayed a negative association with hepatic triglyceride (TG) concentration. These findings suggest that loss of LNCPINT-derived circRNAs may underlie NAFLD via miR-466i-3p- and miR-669c-3p-dependent inactivation of the AMPK signaling pathway.

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miR-3666 inhibits development of hepatic steatosis by negatively regulating PPARγ

Cited by 7 publications

References 33 publications

(−)‑Epigallocatechin‑3‑O‑gallate upregulates the expression levels of miR‑6757‑3p, a suppressor of fibrosis‑related gene expression, in extracellular vesicles derived from human umbilical vein endothelial cells

(−)‑Epigallocatechin‑3‑O‑gallate upregulates the expression levels of miR‑6757‑3p, a suppressor of fibrosis‑related gene expression, in extracellular vesicles derived from human umbilical vein endothelial cells

Peroxisome Proliferator-Activated Receptor-γ as a Target and Regulator of Epigenetic Mechanisms in Nonalcoholic Fatty Liver Disease

Profile analysis and functional modeling identify circular RNAs in nonalcoholic fatty liver disease as regulators of hepatic lipid metabolism

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