Progression of diet induced nonalcoholic steatohepatitis is accompanied by increased expression of kruppel-like-factor 10 in mice

Kim, Ja Kyung; Lee, Kwan Sik; Chang, Heon-Young; Lee, Woon Kyu; Lee, Jung Il

doi:10.1186/1479-5876-12-186

Cited by 23 publications

(19 citation statements)

References 58 publications

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“… a ; Kim et al . ). Our study suggests that in the LBW situation, an activated profibrotic pathway, possibly through hypoxia and/or nutrient deficiency, could set the stage for a sustained activation of a fibrotic pathway into postnatal life.…”

Section: Discussionmentioning

confidence: 97%

The differential effects of low birth weight and Western diet consumption upon early life hepatic fibrosis development in guinea pig

Sarr

Blake

Thompson

et al. 2016

The Journal of Physiology

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Key pointsr Postnatal intake of a high saturated fat/high sugar diet, the Western diet (WD), is a risk factor for liver fibrosis. Recently, adverse in utero conditions resulting in low birth weight (LBW) have also been associated with postnatal fibrosis development.r We demonstrate that suboptimal in utero conditions resulting in LBW are associated with changes in hepatic profibrotic genes in conjunction with minimal liver fibrosis in young non-overweight adult guinea pigs.r Our results also indicate that WD promotes liver steatosis, enhanced expression of hepatic genes and proteins of the proinflammatory, profibrotic, cell death and collagen deposition pathways in conjunction with mild hepatic fibrosis.r Our data highlight that pathways responsible for the initiation of a profibrotic state and ultimately hepatic fibrosis appear different depending upon the insult, an in utero-induced LBW outcome or a postnatal WD exposure.Abstract Postnatal intake of an energy dense diet, the Western diet (WD), is a strong risk factor for liver fibrosis. Recently, adverse in utero conditions resulting in low birth weight (LBW) have also been associated with postnatal fibrosis development. We assessed the independent and possible synergistic effects of placental insufficiency-induced LBW and postnatal WD consumption on liver fibrosis in early adulthood, with a specific focus on changes in inflammation and apoptosis pathways in association with fibrogenesis. Male LBW (uterine artery ablation) and normal birth weight (NBW) guinea pig pups were fed either a control diet (CD) or WD from weaning to 150 days. Significant steatosis, mild lobular inflammation, apoptosis and mild stage 1 fibrosis (perisinusoidal or portal) were evident in WD-fed offspring (NBW/WD and LBW/WD). In LBW/CD versus NBW/CD offspring, increased transforming growth factor-beta 1 and matrix metallopeptidase mRNA and sma-and Mad-related protein 4 (SMAD4) were present in conjunction with minimal stage 1 portal fibrosis. Further, connective tissue growth factor mRNA was increased and miR-146a expression decreased in LBW offspring, irrespective of diet. Independent of birth weight, WD-fed offspring exhibited increased expression of fibrotic genes as well as elevated inflammatory and apoptotic markers. Moreover, the augmented expression of collagen, type III, alpha 1 and tumor necrosis factor-alpha was associated with increased recruitment of RNA polymerase II and enhanced histone acetylation (K9) to their respective promoters. These data support a role for both LBW and postnatal WD as factors contributing to hepatic fibrosis development in offspring through distinct pathways.

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Section: Discussionmentioning

confidence: 97%

The differential effects of low birth weight and Western diet consumption upon early life hepatic fibrosis development in guinea pig

Sarr

Blake

Thompson

et al. 2016

The Journal of Physiology

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“…In contrast, a high fat diet increased the FFA supply from dietary fat and induced Mttp expression [ 17 ]. The High fat diet suppressed ChREBP transcriptional activity [ 44 ]. Moreover, Chrebp deletion did not prevent from high fat diet induced fatty liver owing to decreased fatty acid oxidation [ 19 , 43 ].…”

Section: Discussionmentioning

confidence: 99%

ChREBP Rather Than SHP Regulates Hepatic VLDL Secretion

et al. 2018

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The regulation of hepatic very-low-density lipoprotein (VLDL) secretion plays an important role in the pathogenesis of dyslipidemia and fatty liver diseases. VLDL is controlled by hepatic microsomal triglyceride transfer protein (MTTP). Mttp is regulated by carbohydrate response element binding protein (ChREBP) and small heterodimer partner (SHP). However, it is unclear whether both coordinately regulate Mttp expression and VLDL secretion. Here, adenoviral overexpression of ChREBP and SHP in rat primary hepatocytes induced and suppressed Mttp mRNA, respectively. However, Mttp induction by ChREBP was much more potent than suppression by SHP. Promoter assays of Mttp and the liver type pyruvate kinase gene revealed that SHP and ChREBP did not affect the transcriptional activity of each other. Mttp mRNA and protein levels of Shp−/− mice were similar to those of wild-types; however, those of Chrebp−/−Shp−/− and Chrebp−/− mice were significantly much lower. Consistent with this, the VLDL particle number and VLDL secretion rates in Shp−/− mice were similar to wild-types but were much lower in Chrebp−/− and Chrebp−/−Shp−/− mice. These findings suggest that ChREBP, rather than SHP, regulates VLDL secretion under normal conditions and that ChREBP and SHP do not affect the transcriptional activities of each other.

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“…Similarly, in rat primary hepatocytes KLF10 expression is activated by glucose stimulation and hampered by dominant negative Mlx [17]. Elevated KLF10 expression is also observed in vivo in mouse following feeding on a high fat/high sugar diet [18].…”

Section: Chrebp/mondo-mlx Controls a Gene Regulatory Networkmentioning

confidence: 94%

Sugar sensing by ChREBP/Mondo-Mlx — new insight into downstream regulatory networks and integration of nutrient-derived signals

Havula

Hietakangas

2018

Current Opinion in Cell Biology

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Animals regulate their physiology with respect to nutrient status, which requires nutrient sensing pathways. Simple carbohydrates, sugars, are sensed by the basic-helix-loop-helix leucine zipper transcription factors ChREBP/Mondo, together with their heterodimerization partner Mlx, which are well-established activators of sugar-induced lipogenesis. Loss of ChREBP/Mondo-Mlx in mouse and Drosophila leads to sugar intolerance, that is, inability to survive on sugar containing diet. Recent evidence has revealed that ChREBP/Mondo-Mlx responds to sugar and fatty acid-derived metabolites through several mechanisms and cross-connects with other nutrient sensing pathways. ChREBP/Mondo-Mlx controls several downstream transcription factors and hormones, which mediate not only readjustment of metabolic pathways, but also control feeding behavior, intestinal digestion, and circadian rhythm.

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Progression of diet induced nonalcoholic steatohepatitis is accompanied by increased expression of kruppel-like-factor 10 in mice

Cited by 23 publications

References 58 publications

The differential effects of low birth weight and Western diet consumption upon early life hepatic fibrosis development in guinea pig

The differential effects of low birth weight and Western diet consumption upon early life hepatic fibrosis development in guinea pig

ChREBP Rather Than SHP Regulates Hepatic VLDL Secretion

Sugar sensing by ChREBP/Mondo-Mlx — new insight into downstream regulatory networks and integration of nutrient-derived signals

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