AQP3 is regulated by PPARγ and JNK in hepatic stellate cells carrying PNPLA3 I148M

Tardelli, Matteo; Bruschi, Francesca Virginia; Claudel, Thierry; Moreno-Viedma, Verónica; Halilbasic, Emina; Marra, Fabio; Herac, Merima; Stulnig, Thomas M.; Trauner, Michael

doi:10.1038/s41598-017-14557-9

Cited by 17 publications

(19 citation statements)

References 51 publications

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“…Nuclei were counterstained with DAPI (Sigma‐Aldrich) and mounted (VECTASHIELD® Mounting Medium, Vector Laboratories) for microscope analysis (Olympus BX51). Relative quantification of IF staining was performed using Image J software in an automated fashion as seen previously . Channels were splitted for the respective fluorochrome (Red for PNPLA3 and Green for α‐SMA), and total fluorescence was quantified using macros in parallel for all the pictures taken.…”

Section: Methodsmentioning

confidence: 99%

Metabolic regulation of hepatic PNPLA3 expression and severity of liver fibrosis in patients with NASH

Bruschi

Tardelli

Herac

et al. 2020

Liver International

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Background and Aims The genetic PNPLA3 polymorphism I148M has been extensively associated with higher risk for development and progression of NAFLD towards NASH. Methods PNPLA3 and α‐SMA expression were quantified in liver biopsies collected from NASH patients (n = 26) with different fibrosis stages and PNPLA3 genotypes. To study the potential mechanisms driving PNPLA3 expression during NASH progression towards fibrosis, hepatocytes and hepatic stellate cells (HSCs) were cultivated in low and high glucose medium. Moreover, hepatocytes were treated with increasing concentrations of palmitic acid alone or in combination with glucose. Conditioned media were collected from challenged hepatocytes to stimulate HSCs. Results Tissue expression of PNPLA3 was significantly enhanced in biopsies of patients carrying the I148M polymorphism compared to wild type (WT). In NASH biopsies, PNPLA3 significantly correlated with fibrosis stage and α‐SMA levels independently of PNPLA3 genotype. In line, PNPLA3 expression was higher in α‐SMA positive cells. Low glucose increased PNPLA3 in HSCs, whereas high glucose induced PNPLA3 and de‐novo lipogenesis‐related genes expression in hepatocytes. Palmitic acid induced fat accumulation and cell stress markers in hepatocytes, which could be counteracted by oleic acid. Conditioned media collected from lipotoxic challenged hepatocytes markedly induced PNPLA3 mRNA and protein levels, fibrogenic and autophagic markers and promoted migration in HSCs. Notably, conditioned media collected from hepatocytes cultivated with both glucose and palmitic acid exacerbated HSCs migration, PNPLA3 and fibrogenic gene expression, promoting release of cytokines from HSCs. Conclusions Collectively, our observations uncover the diverse metabolic regulation of PNPLA3 among different hepatic cell populations and support its relation to fibrosis progression.

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Section: Methodsmentioning

confidence: 99%

Metabolic regulation of hepatic PNPLA3 expression and severity of liver fibrosis in patients with NASH

Bruschi

Tardelli

Herac

et al. 2020

Liver International

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“…After AQP3 was silenced, the expression of the classic adipogenic factor PPARγ was significantly inhibited. PPARγ is an indispensable transcription factor for adipocyte differentiation [34], and a previous study has shown that AQP3 is the target of PPARγ in murine adipose cell line [35] and hepatic stellate cells [36]. The level of phosphorylation of AKT was also decreased, which indicates that the downstream signal of the classic insulin signaling pathway is weakened.…”

Section: Discussionmentioning

confidence: 92%

AQP3 Facilitates Proliferation and Adipogenic Differentiation of Porcine Intramuscular Adipocytes

Wang

Yang

Yao

et al. 2020

Genes

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The meat quality of animal products is closely related to the intramuscular fat content. Aquaglyceroporin (AQP) defines a class of water/glycerol channels that primarily facilitate the passive transport of glycerol and water across biological membranes. In this study, the AQP3 protein of the AQP family was mainly studied in the adipogenic function of intramuscular adipocytes in pigs. Here, we found that AQP3 was increased at both mRNA and protein levels upon adipogenic stimuli in porcine intramuscular adipocytes in vitro. Western blot results showed knockdown of AQP3 by siRNA significantly suppressed the expression of adipogenic genes (PPARγ, aP2, etc.), repressed Akt phosphorylation, as well as reducing lipid accumulation. Furthermore, deletion of AQP3 by siRNA significantly downregulated expression of cell cycle genes (cyclin D, E), and decreased the number of EdU-positive cells as well as cell viability. Collectively, our data indicate that AQP3 is of great importance in both adipogenic differentiation and proliferation in intramuscular adipocytes, providing a potential target for modulating fat infiltration in skeletal muscles.

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“…For immunofluorescence, slides were incubated with a cluster of differentiation 11b (CD11b) peridinin chlorophyll protein, cyanine 5.5–labeled antimouse (Mac‐1α chain, M1/70) (BD Biosciences) and counterstained with 4′,6‐diamidino‐2‐phenylindole (Sigma). Relative quantification of immunofluorescent staining was performed using Image J software in an automated fashion …”

Section: Methodsmentioning

confidence: 99%

Monoacylglycerol Lipase Inhibition Protects From Liver Injury in Mouse Models of Sclerosing Cholangitis

et al. 2019

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BaCKgRoUND aND aIMS:Monoacylglycerol lipase (MGL) is the last enzymatic step in triglyceride degradation, hydrolyzing monoglycerides into glycerol and fatty acids (FAs) and converting 2-arachidonoylglycerol into arachidonic acid, thus providing ligands for nuclear receptors as key regulators of hepatic bile acid (BA)/lipid metabolism and inflammation. We aimed to explore the role of MGL in the development of cholestatic liver and bile duct injury in mouse models of sclerosing cholangitis, a disease so far lacking effective pharmacological therapy. appRoaCH aND ReSUltS: To this aim we analyzed the effects of 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) feeding to induce sclerosing cholangitis in wild-type (WT) and knockout (MGL −/− ) mice and tested pharmacological inhibition with JZL184 in the multidrug resistance protein 2 knockout (Mdr2 −/− ) mouse model of sclerosing cholangitis. Cholestatic liver injury and fibrosis were assessed by serum biochemistry, liver histology, gene expression, and western blot characterization of BA and FA synthesis/ transport. Moreover, intestinal FAs and fecal microbiome were analyzed. Transfection and silencing were performed in Caco2 cells. MGL −/− mice were protected from DDC-induced biliary fibrosis and inflammation with reduced serum liver enzymes and increased FA/BA metabolism and β-oxidation. Notably, pharmacological ( JZL184) inhibition of MGL ameliorated cholestatic injury in DDC-fed WT mice and protected Mdr2 −/− mice from spontaneous liver injury, with improved liver enzymes, inflammation, and biliary fibrosis. In vitro experiments confirmed that silencing of MGL decreases prostaglandin E 2 accumulation in the intestine and up-regulates peroxisome proliferator-activated receptors alpha and gamma activity, thus reducing inflammation.CoNClUSIoNS: Collectively, our study unravels MGL as a metabolic target, demonstrating that MGL inhibition may be considered as potential therapy for sclerosing cholangitis.

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AQP3 is regulated by PPARγ and JNK in hepatic stellate cells carrying PNPLA3 I148M

Cited by 17 publications

References 51 publications

Metabolic regulation of hepatic PNPLA3 expression and severity of liver fibrosis in patients with NASH

Metabolic regulation of hepatic PNPLA3 expression and severity of liver fibrosis in patients with NASH

AQP3 Facilitates Proliferation and Adipogenic Differentiation of Porcine Intramuscular Adipocytes

Monoacylglycerol Lipase Inhibition Protects From Liver Injury in Mouse Models of Sclerosing Cholangitis

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