scholarly journals Mechanisms of liver injury in high fat sugar diet fed mice that lack hepatocyte X-box binding protein 1

PLoS ONE ◽  
2022 ◽  
Vol 17 (1) ◽  
pp. e0261789
Author(s):  
Xiaoying Liu ◽  
Sarah A. Taylor ◽  
Kyle D. Gromer ◽  
Danny Zhang ◽  
Susan C. Hubchak ◽  
...  
Keyword(s):  
Liver Disease ◽  
Liver Injury ◽  
Cell Activation ◽  
Stellate Cell ◽  
Binding Protein ◽  
The United States ◽  
High Fat ◽  
Altered Expression ◽  
Nonalcoholic Fatty Liver ◽  
End Stage

Nonalcoholic fatty liver disease (NAFLD) is one of the most common causes of liver diseases in the United States and can progress to cirrhosis, end-stage liver disease and need for liver transplantation. There are limited therapies for NAFLD, in part, due to incomplete understanding of the disease pathogenesis, which involves different cell populations in the liver. Endoplasmic reticulum stress and its adaptative unfolded protein response (UPR) signaling pathway have been implicated in the progression from simple hepatic steatosis to nonalcoholic steatohepatitis (NASH). We have previously shown that mice lacking the UPR protein X-box binding protein 1 (XBP1) in the liver demonstrated enhanced liver injury and fibrosis in a high fat sugar (HFS) dietary model of NAFLD. In this study, to better understand the role of liver XBP1 in the pathobiology of NAFLD, we fed hepatocyte XBP1 deficient mice a HFS diet or chow and investigated UPR and other cell signaling pathways in hepatocytes, hepatic stellate cells and immune cells. We demonstrate that loss of XBP1 in hepatocytes increased inflammatory pathway expression and altered expression of the UPR signaling in hepatocytes and was associated with enhanced hepatic stellate cell activation after HFS feeding. We believe that a better understanding of liver cell-specific signaling in the pathogenesis of NASH may allow us to identify new therapeutic targets.

Aerobic exercise training as a mitigator of nonalcoholic fatty liver disease related fibrosis

2015 ◽  
Author(s):  
◽  
Melissa A. Linden
Keyword(s):  
Liver Disease ◽  
Exercise Training ◽  
Aerobic Exercise ◽  
Food Restriction ◽  
Cell Activation ◽  
Stellate Cell ◽  
Scar Tissue ◽  
Aerobic Exercise Training ◽  
Nonalcoholic Fatty Liver ◽  
Obese Rats

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT REQUEST OF AUTHOR.] Nonalcoholic steatohepatitis (NASH) is a liver disease that is associated with obesity and is characterized by inflammation and fibrosis (scar tissue) within the liver. This condition is difficult to study in humans, therefore rodent models often are used to better understand factors that cause NASH. Additionally, it is unclear if aerobic exercise training can be used to treat the fibrosis that is associated with NASH. In the present study, lean and hyperphagic,obese rats were fed a diet high in fat, sugar and cholesterol to induce NASH. Hyperphagic, obese rats developed more fibrosis and inflammation within the liver than their lean counterparts, suggesting a more advanced disease state. When animals underwent exercise training or food restriction ([about]25% reduction in daily caloric intake)for 12 weeks, the obese rats had modest improvements in both liver fibrosis and inflammation. These improvements were associated with lowered hepatic stellate cell activation, a cell type in the liver that when activated begins to lay down scar tissue. Interestingly, the inactive, obese rat may actually have had the greatest capacity to turn over fibrotic tissue but this was not enough to overcome the diet-induced fibrosis. It is important to note that although both aerobic exercise training and modest food restriction improved liver health, these animals did not have a complete resolution of the liver disease.

scholarly journals Hepatocyte X-box binding protein 1 deficiency increases liver injury in mice fed a high-fat/sugar diet

2015 ◽  
Vol 309 (12) ◽  
pp. G965-G974 ◽  
Author(s):  
Xiaoying Liu ◽  
Anne S. Henkel ◽  
Brian E. LeCuyer ◽  
Matthew J. Schipma ◽  
Kristy A. Anderson ◽  
...  
Keyword(s):  
Liver Injury ◽  
Fatty Liver ◽  
Cell Injury ◽  
Binding Protein ◽  
High Fat ◽  
Nonalcoholic Fatty Liver ◽  
Hepatic Expression ◽  
Huh7 Cells

Fatty liver is associated with endoplasmic reticulum stress and activation of the hepatic unfolded protein response (UPR). Reduced hepatic expression of the UPR regulator X-box binding protein 1 spliced (XBP1s) is associated with human nonalcoholic steatohepatitis (NASH), and feeding mice a high-fat diet with fructose/sucrose causes progressive, fibrosing steatohepatitis. This study examines the role of XBP1 in nonalcoholic fatty liver injury and fatty acid-induced cell injury. Hepatocyte-specific Xbp1-deficient ( Xbp1−/−) mice were fed a high-fat/sugar (HFS) diet for up to 16 wk. HFS-fed Xbp1−/− mice exhibited higher serum alanine aminotransferase levels compared with Xbp1fl/fl controls. RNA sequencing and Gene Ontogeny pathway analysis of hepatic mRNA revealed that apoptotic process, inflammatory response, and extracellular matrix structural constituent pathways had enhanced activation in HFS-fed Xbp1−/− mice. Liver histology demonstrated enhanced injury and fibrosis but less steatosis in the HFS-fed Xbp1−/− mice. Hepatic Col1a1 and Tgfβ1 gene expression, as well as Chop and phosphorylated JNK (p-JNK), were increased in Xbp1−/− compared with Xbp1fl/fl mice after HFS feeding. In vitro, stable XBP1-knockdown Huh7 cells (Huh7-KD) and scramble control cells (Huh7-SCR) were generated and treated with palmitic acid (PA) for 24 h. PA-treated Huh7-KD cells had increased cytotoxicity measured by lactate dehydrogenase release, apoptotic nuclei, and caspase3/7 activity assays compared with Huh7-SCR cells. CHOP and p-JNK expression was also increased in Huh7-KD cells following PA treatment. In conclusion, loss of XBP1 enhances injury in both in vivo and in vitro models of fatty liver injury. We speculate that hepatic XBP1 plays an important protective role in pathogenesis of NASH.

scholarly journals Liver fatty acid binding protein (L-Fabp) modulates murine stellate cell activation and diet-induced nonalcoholic fatty liver disease

Hepatology ◽  
2013 ◽  
Vol 57 (6) ◽  
pp. 2202-2212 ◽  
Author(s):  
Anping Chen ◽  
Youcai Tang ◽  
Victoria Davis ◽  
Fong-Fu Hsu ◽  
Susan M. Kennedy ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Liver Disease ◽  
Fatty Liver Disease ◽  
Cell Activation ◽  
Fatty Acid Binding Protein ◽  
Stellate Cell ◽  
Liver Fatty Acid ◽  
Fatty Acid Binding ◽  
Nonalcoholic Fatty Liver ◽  
Acid Binding Protein

scholarly journals DNA Methylation in Nonalcoholic Fatty Liver Disease

2020 ◽  
Vol 21 (21) ◽  
pp. 8138
Author(s):  
Jeongeun Hyun ◽  
Youngmi Jung
Keyword(s):  
Dna Methylation ◽  
Liver Disease ◽  
Fatty Liver ◽  
Nonalcoholic Fatty Liver Disease ◽  
Fatty Liver Disease ◽  
The United States ◽  
Hepatic Disorder ◽  
Nonalcoholic Fatty Liver ◽  
End Stage ◽  
Affect Gene Expression

Nonalcoholic fatty liver disease (NAFLD) is a widespread hepatic disorder in the United States and other Westernized countries. Nonalcoholic steatohepatitis (NASH), an advanced stage of NAFLD, can progress to end-stage liver disease, including cirrhosis and liver cancer. Poor understanding of mechanisms underlying NAFLD progression from simple steatosis to NASH has limited the development of effective therapies and biomarkers. An accumulating body of studies has suggested the importance of DNA methylation, which plays pivotal roles in NAFLD pathogenesis. DNA methylation signatures that can affect gene expression are influenced by environmental and lifestyle experiences such as diet, obesity, and physical activity and are reversible. Hence, DNA methylation signatures and modifiers in NAFLD may provide the basis for developing biomarkers indicating the onset and progression of NAFLD and therapeutics for NAFLD. Herein, we review an update on the recent findings in DNA methylation signatures and their roles in the pathogenesis of NAFLD and broaden people’s perspectives on potential DNA methylation-related treatments and biomarkers for NAFLD.

scholarly journals Exogenous PP2A inhibitor exacerbates the progression of nonalcoholic fatty liver disease via NOX2-dependent activation of miR21

2019 ◽  
Vol 317 (4) ◽  
pp. G408-G428 ◽  
Author(s):  
Muayad Albadrani ◽  
Ratanesh K. Seth ◽  
Sutapa Sarkar ◽  
Diana Kimono ◽  
Ayan Mondal ◽  
...  
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Protein Phosphatase ◽  
Fatty Liver Disease ◽  
Cell Activation ◽  
Stellate Cell ◽  
Nonalcoholic Fatty Liver ◽  
Phosphatase 2A ◽  
Pp2a Inhibitor

Nonalcoholic fatty liver disease (NAFLD) is an emerging global pandemic. Though significant progress has been made in unraveling the pathophysiology of the disease, the role of protein phosphatase 2A (PP2A) and its subsequent inhibition by environmental and genetic factors in NAFLD pathophysiology remains unclear. The present report tests the hypothesis that an exogenous PP2A inhibitor leads to hepatic inflammation and fibrogenesis via an NADPH oxidase 2 (NOX2)-dependent pathway in NAFLD. Results showed that microcystin (MC) administration, a potent PP2A inhibitor found in environmental exposure, led to an exacerbation of NAFLD pathology with increased CD68 immunoreactivity, the release of proinflammatory cytokines, and stellate cell activation, a process that was attenuated in mice that lacked the p47phox gene and miR21 knockout mice. Mechanistically, leptin-primed immortalized Kupffer cells (a mimicked model for an NAFLD condition) treated with apocynin or nitrone spin trap 5,5 dimethyl-1- pyrroline N-oxide (DMPO) had significantly decreased CD68 and decreased miR21 and α-smooth muscle actin levels, suggesting the role of NOX2-dependent reactive oxygen species in miR21-induced Kupffer cell activation and stellate cell pathology. Furthermore, NOX2-dependent peroxynitrite generation was primarily responsible for cellular events observed following MC exposure since incubation with phenylboronic acid attenuated miR21 levels, Kupffer cell activation, and inflammatory cytokine release. Furthermore, blocking of the AKT pathway attenuated PP2A inhibitor-induced NOX2 activation and miR21 upregulation. Taken together, we show that PP2A may have protective roles, and its inhibition exacerbates NAFLD pathology via activating NOX2-dependent peroxynitrite generation, thus increasing miR21-induced pathology. NEW & NOTEWORTHY Protein phosphatase 2A inhibition causes nonalcoholic steatohepatitis (NASH) progression via NADPH oxidase 2. In addition to a novel emchanism of action, we describe a new tool to describe NASH histopathology.

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