Sodium Acetate Inhibit TGF-β1-Induced Activation of Hepatic Stellate Cells by Restoring AMPK or c-Jun Signaling

Short-chain fatty acids (SCFAs) are crucial gut microbial metabolites that play a major role in the occurrence and development of hepatic fibrosis (HF). However, the effect of SCFAs on hepatic stellate cells (HSCs), the major pro-fibrogenic cells, is yet undefined. In this study, the effects of three major SCFAs (acetate, propionate, and butyrate) were assessed on the activation of HSCs. LX2 cells were activated with TGF-β1 and treated with sodium acetate (NaA), sodium propionate (NaP), or sodium butyrate (NaB). SCFA treatment significantly reduced the protein levels of α-SMA and the phosphorylation of Smad2 and decreased the mRNA expression of Acta2/Col1a1/Fn in cells compared to the TGF-β1 treatment. Among the three SCFAs, NaA revealed the best efficacy at alleviating TGF-β1-induced LX2 cell activation. Additionally, acetate accumulated in the cells, and G protein-coupled receptor (GPR) 43 silencing did not have any impact on the inhibition of LX2 cell activation by NaA. These findings indicated that NaA enters into the cells to inhibit LX2 cell activation independent of GPR43. The results of phosphokinase array kit and Western blot indicated that NaA increased the AMP-activated protein kinase (AMPK) activation and reduced the phosphorylation of c-Jun in cultured LX2 cells, and siRNA-peroxisome proliferator-activated receptor (PPAR) -γ abolished the inhibitory effects of NaA against TGF-β1-induced LX2 cell activation. In conclusion, this study showed that NaA inhibited LX2 cell activation by activating the AMPK/PPARγ and blocking the c-Jun signaling pathways. Thus, SCFAs might represent a novel and viable approach for alleviating HF.

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Platyconic Acid A, Platycodi Radix-Derived Saponin, Suppresses TGF-β1-Induced Activation of Hepatic Stellate Cells via Blocking SMAD and Activating the PPARγ Signaling Pathway

Cells ◽

10.3390/cells8121544 ◽

2019 ◽

Vol 8 (12) ◽

pp. 1544 ◽

Cited By ~ 2

Author(s):

Jae Ho Choi ◽

Seul Mi Kim ◽

Gi Ho Lee ◽

Sun Woo Jin ◽

Hyun Sun Lee ◽

...

Keyword(s):

Hepatic Stellate Cells ◽

Stellate Cells ◽

Inhibitory Effect ◽

Peroxisome Proliferator ◽

Health Food ◽

Inhibitory Effects ◽

Peroxisome Proliferator Activated Receptor ◽

Ppar Γ ◽

Platycodi Radix ◽

Tgf Β1

Platycodi radix is a widely sold health food worldwide, which contains numerous phytochemicals that are beneficial to health. Previously, we reported that saponin from the roots of Platycodi radix-derived saponin inhibited toxicant-induced liver diseases. Nevertheless, the inhibitory effect of platyconic acid A (PA), the active component of Platycodi radix-derived saponin, on the anti-fibrotic activity involving the SMAD pathway remains unclear. We investigated the inhibitory effects of PA on TGF-β1-induced activation of hepatic stellate cells (HSCs). PA inhibited TGF-β1-enhanced cell proliferation, as well as expression of α-SMA and collagen Iα1 in HSC-T6 cells. PA suppressed TGF-β1-induced smad2/3 phosphorylation and smad binding elements 4 (SBE4) luciferase activity. Reversely, PA restored TGF-β1-reduced expression of smad7 and peroxisome proliferator-activated receptor (PPAR)γ. PA also repressed TGF-β1-induced phosphorylation of Akt and MAPKs. In summary, the results suggest that the inhibitory effect of PA on HSCs occurs through the blocking of SMAD-dependent and SMAD-independent pathways, leading to the suppression of α-SMA and collagen Iα1 expression.

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Disruption of transforming growth factor-β signaling by curcumin induces gene expression of peroxisome proliferator-activated receptor-γ in rat hepatic stellate cells

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00200.2006 ◽

2007 ◽

Vol 292 (1) ◽

pp. G113-G123 ◽

Cited By ~ 56

Author(s):

Shizhong Zheng ◽

Anping Chen

Keyword(s):

Gene Expression ◽

Hepatic Stellate Cells ◽

Molecular Mechanisms ◽

Transforming Growth Factor ◽

Gene Promoter ◽

Stellate Cells ◽

Transforming Growth Factor Β ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Ppar Γ

Activation of hepatic stellate cells (HSC), the major effectors of hepatic fibrogenesis, is coupled with sequential alterations in gene expression, including an increase in receptors for transforming growth factor-β (TGF-β) and a dramatic reduction in the peroxisome proliferator-activated receptor-γ (PPAR-γ). The relationship between them remains obscure. We previously demonstrated that curcumin induced gene expression of PPAR-γ in activated HSC, leading to reducing cell proliferation, inducing apoptosis and suppressing expression of extracellular matrix genes. The underlying molecular mechanisms are largely unknown. We recently observed that stimulation of PPAR-γ activation suppressed gene expression of TGF-β receptors in activated HSC, leading to the interruption of TGF-β signaling. This observation supported our assumption of an antagonistic relationship between PPAR-γ activation and TGF-β signaling in HSC. In this study, we further hypothesize that TGF-β signaling might negatively regulate gene expression of PPAR-γ in activated HSC. The present report demonstrates that exogenous TGF-β1 inhibits gene expression of PPAR-γ in activated HSC, which is eliminated by the pretreatment with curcumin likely by interrupting TGF-β signaling. Transfection assays further indicate that blocking TGF-β signaling by dominant negative type II TGF-β receptor increases the promoter activity of PPAR-γ gene. Promoter deletion assays, site-directed mutageneses, and gel shift assays localize two Smad binding elements (SBEs) in the PPAR-γ gene promoter, acting as curcumin response elements and negatively regulating the promoter activity in passaged HSC. The Smad3/4 protein complex specifically binds to the SBEs. Overexpression of Smad4 dose dependently eliminates the inhibitory effects of curcumin on the PPAR-γ gene promoter and TGF-β signaling. Taken together, these results demonstrate that the interruption of TGF-β signaling by curcumin induces gene expression of PPAR-γ in activated HSC in vitro. Our studies provide novel insights into the molecular mechanisms of curcumin in the induction of PPAR-γ gene expression and in the inhibition of HSC activation.

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Biphasic effect of pioglitazone on isolated human endothelial progenitor cells: Involvement of peroxisome proliferator-activated receptor-γ and transforming growth factor-β1

Thrombosis and Haemostasis ◽

10.1160/th06-10-0593 ◽

2007 ◽

Vol 97 (06) ◽

pp. 988-997 ◽

Cited By ~ 5

Author(s):

Mihail Hristov ◽

Denis Gümbel ◽

Teresa Tejerina ◽

Santiago Redondo ◽

Christian Weber

Keyword(s):

Progenitor Cells ◽

Endothelial Progenitor Cells ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β1 ◽

Peroxisome Proliferator ◽

Endothelial Progenitor ◽

Peroxisome Proliferator Activated Receptor ◽

Ppar Γ ◽

Patients With Diabetes ◽

Tgf Β1

SummaryEndothelial progenitor cells (EPCs) have been implicated in vascular repair and found to be functionally impaired in patients with diabetes. We evaluated the effects of the anti-diabetic drug pioglitazone on human EPC function and the involvement of PPAR-γ and TGF-β1. EPCs in culture were characterized at day 7 by the development of colony-forming units (CFUs) and flow cytometry assessment of differentiation marker (DiI-ac-LDL/lectin, KDR and CD31). Adhesion on fibronectin and fibrinogen in flow was analyzed as functional parameter. Treatment with pioglitazone for 72 hours increased the number of EPC-CFUs, DiI-ac-LDL+/lectin+, CD31+ and KDR+ EPCs at 1 μM but not at 10 μM. Since pioglitazone did not significantly alter proliferation and apoptosis in cultured EPCs, the increase in EPC number was most likely attributable to augmented adhesion and differentiation. Indeed, pioglitazone increased EPC adhesion in flow at 1 μM, an effect prevented by PPAR-γ and β2-integrin blockade. In contrast, pioglitazone did not promote EPC adhesion at 10 μM; however, increased adhesion became evident by co-incubation with a blocking TGF-β1 antibody. As determined by ELISA, pioglitazone induced a persistent increase in TGF-β1 secretion only at 10 μM when a significantly elevated expression of endoglin, the accessory receptor forTGF-β1, was also observed. Taken together, pioglitazone exerts biphasic effects on the function of isolated EPCs, causing a PPAR-γ-dependent stimulation at 1 μM and a TGF-β1-mediated suppression at 10 μM. These results may help to define optimal therapeutic doses of pioglitazone for improving endothelial dysfunction.

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Agouti regulates adipocyte transcription factors

AJP Cell Physiology ◽

10.1152/ajpcell.2001.280.4.c954 ◽

2001 ◽

Vol 280 (4) ◽

pp. C954-C961 ◽

Cited By ~ 37

Author(s):

Randall L. Mynatt ◽

Jacqueline M. Stephens

Keyword(s):

Adipose Tissue ◽

Transgenic Mice ◽

Ectopic Expression ◽

Peroxisome Proliferator ◽

Paracrine Factor ◽

Peroxisome Proliferator Activated Receptor ◽

Protein Levels ◽

Skeletal Mass ◽

Ppar Γ ◽

Obesity And Diabetes

Agouti is a secreted paracrine factor that regulates pigmentation in hair follicle melanocytes. Several dominant mutations cause ectopic expression of agouti, resulting in a phenotype characterized by yellow fur, adult-onset obesity and diabetes, increased linear growth and skeletal mass, and increased susceptibility to tumors. Humans also produce agouti protein, but the highest levels of agouti in humans are found in adipose tissue. To mimic the human agoutiexpression pattern in mice, transgenic mice (aP2-agouti) that express agouti in adipose tissue were generated. The transgenic mice develop a mild form of obesity, and they are sensitized to the action of insulin. We correlated the levels of specific regulators of insulin signaling and adipocyte differentiation with these phenotypic changes in adipose tissue. Signal transducers and activators of transcription (STAT)1, STAT3, and peroxisome proliferator-activated receptor (PPAR)-γ protein levels were elevated in the transgenic mice. Treatment of mature 3T3-L1 adipocytes recapitulated these effects. These data demonstrate that agouti has potent effects on adipose tissue. We hypothesize that agouti increases adiposity and promotes insulin sensitivity by acting directly on adipocytes via PPAR-γ.

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Gut Epithelial Metabolism as a Key Driver of Intestinal Dysbiosis Associated with Noncommunicable Diseases

Infection and Immunity ◽

10.1128/iai.00939-19 ◽

2020 ◽

Vol 88 (7) ◽

Cited By ~ 1

Author(s):

Catherine D. Shelton ◽

Mariana X. Byndloss

Keyword(s):

Microbial Community ◽

Short Chain Fatty Acids ◽

Noncommunicable Diseases ◽

Peroxisome Proliferator ◽

Pathogenic Potential ◽

Peroxisome Proliferator Activated Receptor ◽

Ppar Γ ◽

Diet Induced Obesity ◽

Intestinal Dysbiosis ◽

Epithelial Dysfunction

ABSTRACT In high-income countries, the leading causes of death are noncommunicable diseases (NCDs), such as obesity, cancer, and cardiovascular disease. An important feature of most NCDs is inflammation-induced gut dysbiosis characterized by a shift in the microbial community structure from obligate to facultative anaerobes such as Proteobacteria. This microbial imbalance can contribute to disease pathogenesis by either a depletion in or the production of microbiota-derived metabolites. However, little is known about the mechanism by which inflammation-mediated changes in host physiology disrupt the microbial ecosystem in our large intestine leading to disease. Recent work by our group suggests that during gut homeostasis, epithelial hypoxia derived from peroxisome proliferator-activated receptor γ (PPAR-γ)-dependent β-oxidation of microbiota-derived short-chain fatty acids limits oxygen availability in the colon, thereby maintaining a balanced microbial community. During inflammation, disruption in gut anaerobiosis drives expansion of facultative anaerobic Enterobacteriaceae, regardless of their pathogenic potential. Therefore, our research group is currently exploring the concept that dysbiosis-associated expansion of Enterobacteriaceae can be viewed as a microbial signature of epithelial dysfunction and may play a greater role in different models of NCDs, including diet-induced obesity, atherosclerosis, and inflammation-associated colorectal cancer.

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