3,5-Diiodo-L-Thyronine Modifies the Lipid Droplet Composition in a Model of Hepatosteatosis

Grasselli, Elena; Voci, Adriana; Canesi, Laura; Salis, Annalisa; Damonte, Gianluca; Compalati, Andrea D.; Goglia, Fernando; Gallo, Gabriella; Vergani, Laura

doi:10.1159/000356674

Cited by 33 publications

(28 citation statements)

References 58 publications

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“…In contrast to the control group cultured by Dulbecco's modified Eagle's medium (DMEM, HyClone Laboratories, Inc., USA), penicillin-streptomycin, and 10% fetal bovine serum (FBS, Gibco BRL, USA), HepG2 cell in the model group were incubated additionally with 0.5 mM free fatty acid (FFA, oleate : palmitate = 2 : 1; Sigma-Aldrich, USA) dissolved in dimethyl sulfoxide (DMSO) [19]. …”

Section: Methodsmentioning

confidence: 99%

Circular RNA Profiling and Bioinformatic Modeling Identify Its Regulatory Role in Hepatic Steatosis

Guo

Wang

et al. 2017

BioMed Research International

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Circular RNAs (circRNAs) exhibit a wide range of physiological and pathological activities. To uncover their role in hepatic steatosis, we investigated the expression profile of circRNAs in HepG2-based hepatic steatosis induced by high-fat stimulation. Differentially expressed circRNAs were subjected to validation using QPCR and functional analyses using principal component analysis, hierarchical clustering, target prediction, gene ontology (GO), and pathway annotation, respectively. Bioinformatic integration established the circRNA-miRNA-mRNA regulatory network so as to identify the mechanisms underlying circRNAs' metabolic effect. Here we reported that hepatic steatosis was associated with a total of 357 circRNAs. Enrichment of transcription-related GOs, especially GO: 0006355, GO: 004589, GO: 0045944, GO: 0045892, and GO: 0000122, demonstrated their specific actions in transcriptional regulation. Lipin 1 (LPIN1) was recognized to mediate the transcriptional regulatory effect of circRNAs on metabolic pathways. circRNA-miRNA-mRNA network further identified the signaling cascade of circRNA_021412/miR-1972/LPIN1, which was characterized by decreased level of circRNA_021412 and miR-1972-based inhibition of LPIN1. LPIN1-induced downregulation of long chain acyl-CoA synthetases (ACSLs) expression finally resulted in the hepatosteatosis. These findings identify circRNAs to be important regulators of hepatic steatosis. Transcription-dependent modulation of metabolic pathways may underlie their effects, partially by the circRNA_021412/miR-1972/LPIN1 signaling.

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Section: Methodsmentioning

confidence: 99%

Circular RNA Profiling and Bioinformatic Modeling Identify Its Regulatory Role in Hepatic Steatosis

Guo

Wang

et al. 2017

BioMed Research International

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“…To investigate the effect of lipid droplets accumulation on ACLY expression, HepG2 cells were cultured in a medium supplemented with 0.75 mM FFAs up to 48 h. The concentration of FFAs (0.75 mM) is in the range of plasmatic FFAs levels in patients with NAFLD [9,23]. This treatment did not affect cell viability (data not shown).…”

Section: Acly Expression Changes In Hepg2 Cells Upon Lipid Accumulationmentioning

confidence: 99%

In Steatotic Cells, ATP-Citrate Lyase mRNA Is Efficiently Translated through a Cap-Independent Mechanism, Contributing to the Stimulation of De Novo Lipogenesis

Siculella

Giannotti

Testini

et al. 2020

IJMS

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Non-alcoholic fatty liver disease (NAFLD) is a chronic disease in which excessive amount of lipids is accumulated as droplets in hepatocytes. Recently, cumulative evidences suggested that a sustained de novo lipogenesis can play an important role in NAFLD. Dysregulated expression of lipogenic genes, including ATP-citrate lyase (ACLY), has been found in liver diseases associated with lipid accumulation. ACLY is a ubiquitous cytosolic enzyme positioned at the intersection of nutrients catabolism and cholesterol and fatty acid biosyntheses. In the present study, the molecular mechanism of ACLY expression in a cell model of steatosis has been reported. We identified an internal ribosome entry site (IRES) in the 5 untranslated region of the ACLY mRNA, that can support an efficient mRNA translation through a Cap-independent mechanism. In steatotic HepG2 cells, ACLY expression was up-regulated through IRES-mediated translation. Since it has been demonstrated that lipid accumulation in cells induces endoplasmic reticulum (ER) stress, the involvement of this cellular pathway in the translational regulation of ACLY has been also evaluated. Our results showed that ACLY expression was increased in ER-stressed cells, through IRES-mediated translation of ACLY mRNA. A potential role of the Cap-independent translation of ACLY in NAFLD has been discussed. Int. J. Mol. Sci. 2020, 21, 1206 48 h of treatment ( Figure 1B). In agreement with previous results [9], treatment with FFAs caused an increment of SREBP-1 mRNA abundance ( Figure 1A). The content of precursor (pSREBP-1) and active nuclear (nSREBP-1) of SREBP-1 protein increased in FFAs-treated cells with respect to control ( Figure 1B). Int. J. Mol. Sci. 2020, 21, 1206 Then ACLY levels showed a constant increase, becoming about 3.5-fold greater than the control after 48 h of treatment ( Figure 1B). In agreement with previous results [9], treatment with FFAs caused an increment of SREBP-1 mRNA abundance ( Figure 1A). The content of precursor (pSREBP-1) and active nuclear (nSREBP-1) of SREBP-1 protein increased in FFAs-treated cells with respect to control ( Figure 1B).

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“…In in vitro model of hepatosteatosis, T2 stimulates the mitochondrial oxidation by up-regulating carnitine-palmitoyl-transferase (CPT1), uncoupling protein 2 (UCP2) and very long-chain acyl-coenzyme A dehydrogenase (VLCAD) [106]. By activating mitochondrial oxidative metabolism of fatty acids, in particular of saturated fatty acids, T2 reduces the number and size of LDs, and modifies their acyl composition by decreasing the content of saturated vs. monounsaturated fatty acids [106] (Table 2). …”

Section: T2 and Its Effects On Dnlmentioning

confidence: 99%

Action of Thyroid Hormones, T3 and T2, on Hepatic Fatty Acids: Differences in Metabolic Effects and Molecular Mechanisms

Damiano

Rochira

Gnoni

et al. 2017

IJMS

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The thyroid hormones (THs) 3,3′,5,5′-tetraiodo-l-thyronine (T4) and 3,5,3′-triiodo-l-thyronine (T3) influence many metabolic pathways. The major physiological function of THs is to sustain basal energy expenditure, by acting primarily on carbohydrate and lipid catabolism. Beyond the mobilization and degradation of lipids, at the hepatic level THs stimulate the de novo fatty acid synthesis (de novo lipogenesis, DNL), through both the modulation of gene expression and the rapid activation of cell signalling pathways. 3,5-Diiodo-l-thyronine (T2), previously considered only a T3 catabolite, has been shown to mimic some of T3 effects on lipid catabolism. However, T2 action is more rapid than that of T3, and seems to be independent of protein synthesis. An inhibitory effect on DNL has been documented for T2. Here, we give an overview of the mechanisms of THs action on liver fatty acid metabolism, focusing on the different effects exerted by T2 and T3 on the regulation of the DNL. The inhibitory action on DNL exerted by T2 makes this compound a potential and attractive drug for the treatment of some metabolic diseases and cancer.

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3,5-Diiodo-L-Thyronine Modifies the Lipid Droplet Composition in a Model of Hepatosteatosis

Cited by 33 publications

References 58 publications

Circular RNA Profiling and Bioinformatic Modeling Identify Its Regulatory Role in Hepatic Steatosis

Circular RNA Profiling and Bioinformatic Modeling Identify Its Regulatory Role in Hepatic Steatosis

In Steatotic Cells, ATP-Citrate Lyase mRNA Is Efficiently Translated through a Cap-Independent Mechanism, Contributing to the Stimulation of De Novo Lipogenesis

Action of Thyroid Hormones, T3 and T2, on Hepatic Fatty Acids: Differences in Metabolic Effects and Molecular Mechanisms

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