American journal of physiology. Gastrointestinal and liver physiology
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Am. J. Physiol. Gastrointest. Liver Physiol. · Apr 2019
Hepatic transcriptome signatures in patients with varying degrees of nonalcoholic fatty liver disease compared with healthy normal-weight individuals.
Nonalcoholic fatty liver disease (NAFLD) represents a spectrum of conditions ranging from simple steatosis (NAFL), over nonalcoholic steatohepatitis (NASH) with or without fibrosis, to cirrhosis with end-stage disease. The hepatic molecular events underlying the development of NAFLD and transition to NASH are poorly understood. The present study aimed to determine hepatic transcriptome dynamics in patients with NAFL or NASH compared with healthy normal-weight and obese individuals. ⋯ NEW & NOTEWORTHY Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in Western countries. NAFLD is associated with the metabolic syndrome and can progress to the more serious form, nonalcoholic steatohepatitis (NASH), and ultimately lead to irreversible liver damage. Using gold standard molecular and histological techniques, this study demonstrates that the currently used diagnostic tools are problematic for differentiating mild NAFLD from NASH and emphasizes the marked need for developing improved histological markers of NAFLD progression.
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Am. J. Physiol. Gastrointest. Liver Physiol. · Apr 2019
lncRNA GAS5 restrains CCl4-induced hepatic fibrosis by targeting miR-23a through the PTEN/PI3K/Akt signaling pathway.
Hepatic fibrosis is chronic liver damage with many causes that has a relatively high death rate. The current study showed that long noncoding RNA (lncRNA) growth arrest-specific transcript 5 (GAS5), microRNA-23a (miR-23a), and phosphatase and tensin homolog (PTEN) play important roles in the pathological process of hepatic fibrosis but have a relatively unclear regulatory mechanism. This study aimed to investigate the roles of lncRNA GAS5, miR-23a, and PTEN in the pathological process of hepatic fibrosis and hepatic stellate cell (HSC) activation. ⋯ We revealed the role of the lncRNA GAS5/miR-23a/PTEN/PI3K/Akt/mTOR/Snail signaling pathway in hepatic fibrosis, providing molecular targets for the treatment of hepatic fibrosis. NEW & NOTEWORTHY This is the first study revealing that microRNA-23a (miR-23a) promotes hepatic fibrosis through the phosphatase and tensin homolog/phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin/Snail signaling pathway, and long noncoding RNA (lncRNA) growth arrest-specific transcript 5 (GAS5) can act as a sponge platform for miR-23a. Therefore, lncRNA GAS5/miR-23a may bring molecular targets for hepatic fibrosis therapy.
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Am. J. Physiol. Gastrointest. Liver Physiol. · Mar 2019
Histamine-mediated potentiation of transient receptor potential (TRP) ankyrin 1 and TRP vanilloid 4 signaling in submucosal neurons in patients with irritable bowel syndrome.
Previously, we showed histamine-mediated sensitization of transient receptor potential (TRP) vanilloid 1 (TRPV1) in patients with irritable bowel syndrome (IBS). Sensitization of TRP ankyrin 1 (TRPA1) and TRP vanilloid 4 (TRPV4) are also involved in aberrant pain perception in preclinical models of somatic pain. Here, we hypothesize that in parallel with TRPV1, histamine sensitizes TRPA1 and TRPV4, contributing to increased visceral pain in patients with IBS. ⋯ These data further underscore H1R antagonism as potential treatment for IBS. NEW & NOTEWORTHY We provide evidence for histamine-mediated transient receptor potential (TRP) ankyrin 1 and TRP vanilloid 4 sensitization in irritable bowel syndrome (IBS) via histamine 1 receptor (H1R) activation, most likely contributing to increased visceral pain perception. Our results reveal a general role of sensory TRP channels as histamine effectors in the pathophysiology of IBS and provide novel mechanistic insights into the therapeutic potential of H1R antagonism in IBS.
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Am. J. Physiol. Gastrointest. Liver Physiol. · Jan 2019
A novel role for programmed cell death receptor ligand 2 in sepsis-induced hepatic dysfunction.
The liver is an organ that, when dysfunctional in a septic patient, is strongly associated with morbidity and mortality. Understanding the pathophysiology of liver failure during sepsis may lead to improved diagnostics and potential therapeutic targets. Historically, programmed cell death receptor (PD) ligand 1 (PD-L1) has been considered the primary ligand for its checkpoint molecule counterpart, PD-1, with PD-L2 rarely in the immunopathological spotlight. ⋯ Taken together, these data suggest that although PD-L2 has some selective effects on the hepatic response seen in the septic mouse, these factors are not sufficient to alter septic mortality in this adult murine model. NEW & NOTEWORTHY Our study shows not only that ligands of the checkpoint protein PD-1 respond inversely to a stressor such as septic challenge (PD-L2 declines, whereas PD-L1 rises) but also that aspects of liver dysfunction increase in septic mice lacking the PD-L2 gene. Furthermore, these differences in PD-L2 gene-deficient animals culminated in the abrogation of the survival advantage seen in the septic PD-L1-knockout mice, suggesting that PD-L2 may have roles beyond a simple immune tolerogen.
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Am. J. Physiol. Gastrointest. Liver Physiol. · Jan 2019
Acute administration of IL-6 improves indices of hepatic glucose and insulin homeostasis in lean and obese mice.
Obesity can lead to impairments in hepatic glucose and insulin homeostasis, and although exercise is an effective treatment, the molecular targets remain incompletely understood. As IL-6 is an exercise-inducible cytokine, we aimed to identify whether IL-6 itself influences hepatic glucose and insulin homeostasis and whether this response differs during obesity. In vivo, male mice were fed a low-fat diet (LFD; 10% kcal) or a high-fat diet (HFD; 60% kcal) for 7 wk, which induced obesity and hepatic lipid accumulation. ⋯ NEW & NOTEWORTHY In this study, we used lean and obese mice and found that a single injection of IL-6 improved glucose tolerance, decreased hepatic gluconeogenic gene expression, and increased hepatic phosphorylation of AKT. In primary hepatocytes cultured under control and lipid-laden conditions, IL-6 had a mild, but deleterious, effect on phosphorylation of AKT. Our results show that the beneficial effects of IL-6 on glucose and insulin homeostasis, in vivo, are maintained in obesity.