Oxidative stress, KLF6 and transforming growth factor-β up-regulation differentiate non-alcoholic steatohepatitis progressing to fibrosis from uncomplicated steatosis in rats

Stärkel, Peter; Sempoux, Christine; Leclercq, Isabelle; Hérin, Michel; Deby, C.; Desager, Jean‐Pierre; Horsmans, Yves

doi:10.1016/s0168-8278(03)00360-x

Cited by 125 publications

(111 citation statements)

References 29 publications

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“…12 Previous studies have suggested that KLF6 regulates cell proliferation, development, remodeling, and response to injury. 15,[17][18][19] Relevant to the present studies, KLF6 has been shown to be induced in hepatic steatosis rats 18 and to directly transactivate transforming growth factor-␤ signaling. 43 In recent studies we demonstrated that KLF6 expression is increased in the tubules of diabetic Ren-2 rats undergoing epithelial to mesenchymal transformation, which contributes significantly to the interstitial fibrotic process in diabetic nephropathy.…”

Section: Discussionmentioning

confidence: 73%

“…15,16 KLF6 is known to be expressed in embryonic kidney 17 but, interestingly, was found to be up-regulated in injured hepatic stellate cells 18 and in the kidneys of mice undergoing ischemic reperfusion injury. 19 Because embryonic transcription factors and proteins are re-expressed in renal injury, 20 we initially explored whether KLF6 expression is recapitulated in diabetic nephropathy.…”

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confidence: 99%

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Transcription Factors Krüppel-Like Factor 6 and Peroxisome Proliferator-Activated Receptor-γ Mediate High Glucose-Induced Thioredoxin-Interacting Protein

Chen

Holian

et al. 2009

The American Journal of Pathology

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We demonstrated recently that thioredoxin-interacting protein (Txnip) and the transcription factor Krüp-pel-like factor 6 (KLF6) were up-regulated in both in vivo and in vitro models of diabetic nephropathy, thus promoting renal injury. Conversely, peroxisome proliferator-activated receptor-␥ (PPAR-␥) agonists have been shown to be renoprotective. Hence, this study was undertaken to determine whether Txnip expression is regulated by the transcription factors KLF6 and PPAR-␥. By using siRNAs and overexpressing constructs, the role of KLF6 and PPAR-␥ in Txnip transcriptional regulation was determined in human kidney proximal tubule cells and in streptozocin-induced diabetes mellitus in Sprague-Dawley rats, in vitro and in vivo models of diabetic nephropathy, respectively. KLF6 overexpression increased Txnip expression and promoter activity, which was inhibited by concurrent exposure to PPAR-␥ agonists. In contrast, reduced expression of KLF6 by siRNA or exposure to PPAR-␥ agonists attenuated high glucoseinduced Txnip expression and promoter activity. KLF6-Txnip promoter binding was decreased in KLF6-silenced cells, whereas PPAR-␥ agonists increased PPAR-␥-Txnip promoter binding. Indeed, silencing of KLF6 increased PPAR-␥ expression, suggesting endogenous regulation of PPAR-␥ expression by KLF6. Moreover, renal KLF6 and Txnip expression increased in rats with diabetes mellitus and was inhibited by PPAR-␥ agonist treatment; however, KLF6 expression did not change in HK-2 cells exposed to PPAR-␥ agonists. Hence, Txnip expression and promoter activity are mediated via divergent effects of KLF6 and PPAR-␥ transcriptional regulation.

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Section: Discussionmentioning

confidence: 73%

mentioning

confidence: 99%

Transcription Factors Krüppel-Like Factor 6 and Peroxisome Proliferator-Activated Receptor-γ Mediate High Glucose-Induced Thioredoxin-Interacting Protein

Chen

Holian

et al. 2009

The American Journal of Pathology

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“…Even after 22 weeks of highfat diet the expression levels of key lipogenic markers still differed. Tgfb1 and Pai-1 expression levels in liver were decreased in CH3/HeJ mice, arguing for an effect of the TLR4 pathway, known as a key determinant of non-alcoholic steatohepatitis [50], on the evolution of hepatic fibrosis. Several studies have shown an inverse relationship between hepatic triacylglycerol stores and hepatic insulin sensitivity [11].…”

Section: Discussionmentioning

confidence: 97%

C3H/HeJ mice carrying a toll-like receptor 4 mutation are protected against the development of insulin resistance in white adipose tissue in response to a high-fat diet

et al. 2007

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Aims/hypothesis Inflammation is associated with obesity and has been implicated in the development of diabetes and atherosclerosis. During gram-negative bacterial infection, lipopolysaccharide causes an inflammatory reaction via toll-like receptor 4 (TLR4), which has an essential function in the induction of innate and adaptative immunity. Our aim was to determine what role TLR4 plays in the development of metabolic phenotypes during high-fat feeding. Materials and methods We evaluated metabolic consequences of a high-fat diet in TLR4 mutant mice (C3H/HeJ) and their respective controls. Results TLR4 inactivation reduced food intake without significant modification of body weight, but with higher epididymal adipose tissue mass and adipocyte hypertrophy. It also attenuated the inflammatory response and increased glucose transport and the expression levels of adiponectin and lipogenic markers in white adipose tissue. In addition, TLR4 inactivation blunted insulin resistance induced by lipopolysaccharide in differentiated adipocytes. Increased feeding efficiency in TLR4 mutant mice was associated with lower mass and lower expression of uncoupling protein 1 gene in brown adipose tissue. Finally, TLR4 inactivation slowed the development of hepatic steatosis, reducing the liver triacylglycerol content and also expression levels of lipogenic and fibrosis markers. Conclusions/interpretation TLR4 influences white adipose tissue inflammation and insulin sensitivity, as well as liver fat storage, and is important in the regulation of metabolic phenotype during a fat-enriched diet.

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“…TGF-␤, an important profibrogenic cytokine, is an activator and survival factor for HSCs, and alters gene expression to favor extracellular matrix deposition. Elevated levels of TGF-␤ have been detected in fibrotic human liver, cirrhotic rat liver, and in the livers of rats fed the MCD diet [22] (where TGF-␤ likely plays an important role in the development of hepatic fibrosis [23]. Simultaneously, expression of genes involved in expression of matrix structure such as MMP-9 (gelatinase-B, 8.5-fold), MMP-13 (4-fold), collagen-␣1 (9.2-fold), and SOCS1 were upregulated in deficient animals.…”

Section: Discussionmentioning

confidence: 99%

Glutathione‐enhancing agents protect against steatohepatitis in a dietary model

Chen

et al. 2006

J Biochem & Molecular Tox

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Nonalcoholic fatty liver (NAFL) and steatohepatitis (NASH) may accompany obesity, diabetes, parenteral nutrition, jejeuno-ileal bypass, and chronic inflammatory bowel disease. Currently there is no FDA approved and effective therapy available. We investigated the potential efficacy of those agents that stimulate glutathione (GSH) biosynthesis on the development of experimental steatohepatitis. Rats fed (ad libitum) amino acid based methionine-choline deficient (MCD) diet were further gavaged with (1) vehicle (MCD), (2) S-adenosylmethionine (SAMe), or (3) 2(RS)-n-propylthiazolidine-4(R)-carboxylic acid (PTCA). Results: MCD diet significantly reduced hematocrit, and this abnormality improved in the treated groups ( p < 0.01). Serum transaminases were considerably elevated (AST: 5.8-fold; ALT: 3.22-fold) in MCD rats. However, administration of GSH-enhancing agents significantly suppressed these abnormal enzyme activities. MCD rats developed severe liver pathology manifested by fatty degeneration, inflammation, and necrosis, which significantly improved with therapy. Blood levels of GSH were significantly depleted in MCD rats but normalized in the treated groups. Finally, RT-PCR measurements showed a significant upregulation of genes involved in tissue remodeling and fibrosis (matrix metalloproteinases, collagen-␣1), suppressor of cytokines signaling1, and the inflammatory cytokines (IL-1␤, IL-6, TNF-␣, and TGF-␤) in the livers of rats fed MCD. GSH-enhancing therapies significantly attenuated the expression of deleterious proinflammatory and fibrogenic genes in this dietary model. This is the first report that oral administration of SAMe and PTCA provide protection against liver injury in this model and suggests therapeutic applications of these compounds in NASH patients. C

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Oxidative stress, KLF6 and transforming growth factor-β up-regulation differentiate non-alcoholic steatohepatitis progressing to fibrosis from uncomplicated steatosis in rats

Cited by 125 publications

References 29 publications

Transcription Factors Krüppel-Like Factor 6 and Peroxisome Proliferator-Activated Receptor-γ Mediate High Glucose-Induced Thioredoxin-Interacting Protein

Transcription Factors Krüppel-Like Factor 6 and Peroxisome Proliferator-Activated Receptor-γ Mediate High Glucose-Induced Thioredoxin-Interacting Protein

C3H/HeJ mice carrying a toll-like receptor 4 mutation are protected against the development of insulin resistance in white adipose tissue in response to a high-fat diet

Glutathione‐enhancing agents protect against steatohepatitis in a dietary model

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