Bile acids increase the activity of the epithelial Na+ channel

Wiemuth, Dominik; Lefèvre, Cathérine M. T.; Heidtmann, H.; Gründer, Stefan

doi:10.1007/s00424-013-1403-0

Cited by 20 publications

(19 citation statements)

References 32 publications

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“…This scenario is in agreement with bile acid-sensitivity of the related ENaC [43]. In Xenopus oocytes, there are two populations of ENaC: one with a high open probability P o and one that is nearly silent [44].…”

Section: Discussionsupporting

confidence: 84%

“…In Xenopus oocytes, there are two populations of ENaC: one with a high open probability P o and one that is nearly silent [44]. Interestingly, bile acids further increase P o of already active channels but do not activate silent channels [43]. This is in agreement with the idea that the population of ENaC with an energetically unstable closed state (high P o ) senses bile acids and thus membrane alterations whereas the population with a stable closed state (low P o ) does not.…”

Section: Discussionmentioning

confidence: 99%

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The Bile Acid-Sensitive Ion Channel (BASIC) Is Activated by Alterations of Its Membrane Environment

et al. 2014

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The bile acid-sensitive ion channel (BASIC) is a member of the DEG/ENaC family of ion channels. Channels of this family are characterized by a common structure, their physiological functions and modes of activation, however, are diverse. Rat BASIC is expressed in brain, liver and intestinal tract and activated by bile acids. The physiological function of BASIC and its mechanism of bile acid activation remain a puzzle. Here we addressed the question whether amphiphilic bile acids activate BASIC by directly binding to the channel or indirectly by altering the properties of the surrounding membrane. We show that membrane-active substances other than bile acids also affect the activity of BASIC and that activation by bile acids and other membrane-active substances is non-additive, suggesting that BASIC is sensitive for changes in its membrane environment. Furthermore based on results from chimeras between BASIC and ASIC1a, we show that the extracellular and the transmembrane domains are important for membrane sensitivity.

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Section: Discussionsupporting

confidence: 84%

Section: Discussionmentioning

confidence: 99%

The Bile Acid-Sensitive Ion Channel (BASIC) Is Activated by Alterations of Its Membrane Environment

et al. 2014

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“…Data acquisition and solution exchange were controlled using Cellworks 5. Single Channel Patch Clamp Recordings-Single channel recordings from oocytes were performed as described previously (43). Briefly, 24 -48 h prior to experiments, oocytes were injected with WT rBASIC or ⌬N30 rBASIC coding cRNA (0.008 ng).…”

Section: Methodsmentioning

confidence: 99%

“…Single channel analyses of 10-s recording segments were conducted as described previously (43). Data were analyzed with IgorPro 6.02 (WaveMetrics, Lake Oswego, OR) and are presented as means Ϯ S.E.…”

Section: Methodsmentioning

confidence: 99%

A Cytosolic Amphiphilic α-Helix Controls the Activity of the Bile Acid-sensitive Ion Channel (BASIC)

Schmidt

Löhrer

Alsop

et al. 2016

Journal of Biological Chemistry

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Edited by George CarmanThe bile acid-sensitive ion channel (BASIC) is a member of the degenerin/epithelial Na ؉ channel (Deg/ENaC) family of ion channels. It is mainly found in bile duct epithelial cells, the intestinal tract, and the cerebellum and is activated by alterations of its membrane environment. Bile acids, one class of putative physiological activators, exert their effect by changing membrane properties, leading to an opening of the channel. The physiological function of BASIC, however, is unknown. Deg/ ENaC channels are characterized by a trimeric subunit composition. Each subunit is composed of two transmembrane segments, which are linked by a large extracellular domain. The termini of the channels protrude into the cytosol. Many Deg/ ENaC channels contain regulatory domains and sequence motifs within their cytosolic domains. In this study, we show that BASIC contains an amphiphilic ␣-helical structure within its N-terminal domain. This ␣-helix binds to the cytosolic face of the plasma membrane and stabilizes a closed state. Truncation of this domain renders the channel hyperactive. Collectively, we identify a cytoplasmic domain, unique to BASIC, that controls channel activity via membrane interaction.

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“…Both these genes had a similar trend of gene expression which reduced in WT mice fed a HCD and a further reduction in Hfe -/-mice fed a HCD. Moreover, both these genes have been suppressed by TGF-β1 (243,247,248). Given the differential expression in Hfe -/-mice with the loss of HFE function -a major histocompatibility complex, one can speculate a role for an altered inflammatory response in altered membrane transporters in steatohepatitis.…”

Section: Discussionmentioning

confidence: 99%

Hfe-associated steatohepatitis: expression profiling and identifying the molecular basis of liver injury

Santrampurwala¹

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Non-alcoholic fatty liver disease (NAFLD) is an increasingly common clinical diagnosis and is predicted to become the leading indication for liver transplantation within a decade. Nonalcoholic steatohepatitis (NASH) is the progressive form of NAFLD with a fibro-inflammatory phenotype and can lead to liver cirrhosis. Although the factors responsible for progression from simple steatosis to NASH are unknown, there has been a particular interest in the role of ironinduced oxidative stress in this transition. The HFE protein plays a vital role in maintaining systemic iron homeostasis and a gene mutation in HFE is causative of haemochromatosis. In HFE-haemochromatosis, steatosis is associated with increased liver fibrosis. In keeping with these results, research from our laboratory has previously shown altered lipid metabolism and greater severity of injury in Hfe -/-mice fed a high calorie diet (HCD), which represents a western diet.The primary aim of this project was to enhance the understanding of disease progression inHfe-associated steatohepatitis through the identification and characterisation of genes that are differentially expressed. A gene expression profile was generated by high throughput sequencing of messenger RNA isolated from livers of Hfe -/-mice fed a chow diet and those fed a HCD. Subsequent bioinformatics analysis revealed a list of genes that were significantly altered in response to HCD-induced steatohepatitis. Among the genes that were upregulated are lipid droplet proteins, Perilipin 2 (Plin2) and Cell death inducing DFFA-like effector c (Cidec) which have been previously associated with the development of liver steatosis.Glycosylphosphatidylinositol phospholipase D1 (Gpld1), a high-density lipoprotein, was decreased in NASH livers and was the focus of this study because of the contrary upregulation observed in patients with NAFLD. Arylsulfatase G (Arsg) and Interferon, alpha-inducible protein 27 like 2B (Ifi27l2b) were identified as genes without a previously recognised role in the development of liver injury or fat accumulation and the work in this thesis has primarily focussed on elucidating the underlying roles of these genes in liver injury.To further investigate these genes an in vitro model of hepatocyte fat and iron loading was developed. This model showed gene expression which indicated increased, mitochondrial β-oxidation and reduced fatty acid storage in cells with concomitant free fatty acid (FFA) and iron loading. These changes were also associated with an increase in the pro-inflammatory In this thesis, Gpld1 expression was consistently reduced in AML12 hepatocytes, with all external stimuli, FFA and iron, insulin and inflammation. This downregulation was similar to its expression in rodent NASH livers from transcriptomics analysis and suggests that Gpld1 may influence the extent of injury in iron related steatohepatitis. To the best of my knowledge this is the first study to describe a role for Arsg in response to lipid droplet accumulation and inflammation in hepatocyte...

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Bile acids increase the activity of the epithelial Na+ channel

Cited by 20 publications

References 32 publications

The Bile Acid-Sensitive Ion Channel (BASIC) Is Activated by Alterations of Its Membrane Environment

The Bile Acid-Sensitive Ion Channel (BASIC) Is Activated by Alterations of Its Membrane Environment

A Cytosolic Amphiphilic α-Helix Controls the Activity of the Bile Acid-sensitive Ion Channel (BASIC)

Hfe-associated steatohepatitis: expression profiling and identifying the molecular basis of liver injury

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