Regulation of bile acid receptor activity

Many receptors can be activated by bile acids(BAs)and their derivatives.These include nuclear receptors farnesoid X receptor(FXR),pregnane X receptor(PXR),and vitamin D receptor(VDR),as well as membrane receptors Takeda G protein receptor 5(TGR5),sphingosine-1-phosphate receptor 2(S1PR2),and cholinergic receptor muscarinic 2(CHRM2).All of them are implicated in the development of metabolic and immunological diseases in response to endobiotic and xenobiotic exposure.Because epigenetic regulation is critical for organisms to adapt to constant environmental changes,this review article summarizes epigenetic regulation as well as post-transcriptional modification of bile acid re-ceptors.In addition,the focus of this review is on the liver and digestive tract although these receptors may have effects on other organs.Those regulatory mechanisms are implicated in the disease process and critically important in uncovering innovative strategy for prevention and treatment of metabolic and immunological diseases.

Bidirectional regulation of fragile X mental retardation protein phosphorylation controls rhodopsin hornoeostasis

Homoeostatic regulation of the light sensor, rhodopsin, is critical for the maintenance of light sensitivity and survival of photore- ceptors. The major fly rhodopsin, Rhl, undergoes light-induced endocytosis and degradation, but its protein and mRNA levels remain constant during light/dark cycles. It is not clear how translation of Rhl is regulated. Here, we show that adult photorecep- tors maintain a constant, abundant quantity of ninaE mRNA, which encodes Rhl. We demonstrate that the Fmrl protein associ- ates with ninaE mRNA and represses its translation. Further, light exposure triggers a calcium-dependent dephosphorylation of Fmrl, which relieves suppression of Rhl translation. We demonstrate that Mts, the catalytic subunit of protein phosphatase 2A （PP2A）, mediates light-induced Fmrl dephosphorylation in a regulatory B subunit of PP2A （CKa）-dependent manner. Finally, we show that blocking light-induced Rhl translation results in reduced light sensitivity. Our results reveal the molecular mechanism of Rhl homoeostasis and physiological consequence of Rhl dysregulation.

Bile acids and metabolic surgery

The epidemic of obesity and its co-mortalities has reached an alarming level worldwide.Currently,metabolic surgeries,especially the Roux-en-Y gastric bypass and vertical sleeve gastrectomy,are the most effective and sustainable treatments for obesity,type 2 diabetes,non-alcoholic steatohepatitis,as well as other metabolic diseases.However,the invasive nature of the surgeries limits their broad ap-plications to the general public.Therefore,developing alternative non-invasive approaches to mimic metabolic surgery is an important direction of the field.Recent studies have identified several potential metabolic surgery-induced downstream endocrine mediators,among which bile acids are key candidate signaling molecules.Bile acids are profoundly altered by metabolic surgery,which contributes to the metabolic effects of the surgery.In this review,we focus on the most recent studies on the roles of bile acids and bile acid receptors farnesoid X receptor and Takeda G protein-coupled receptor 5 in mediating the metabolic effects of metabolic surgery.We conclude that targeting bile acid pathways may be a promising pharmacological approach to mimic the beneficial effects of metabolic surgery.

The contributions of bacteria metabolites to the development of hepatic encephalopathy

Over 20%of mortality during acute liver failure is associated with the development of hepatic encephalopathy(HE).Thus,HE is a complication of acute liver failure with a broad spectrum of neuropsychiatric abnormalities ranging from subclinical alterations to coma.HE is caused by the diversion of portal blood into systemic circulation through portosystemic collateral vessels.Thus,the brain is exposed to intestinal-derived toxic substances.Moreover,the strategies to prevent advancement and improve the prognosis of such a liver-brain disease rely on intestinal microbial modulation.This is supported by the findings that antibiotics such as rifaximin and laxative lactulose can alleviate hepatic cirrhosis and/or prevent HE.Together,the significance of the gut-liver-brain axis in human health warrants attention.This review paper focuses on the roles of bacteria metabolites,mainly ammonia and bile acids(BAs)as well as BA receptors in HE.The literature search conducted for this review included searches for phrases such as BA receptors,BAs,ammonia,farnesoid X receptor(FXR),G protein-coupled bile acid receptor 1(GPBAR1 or TGR5),sphingosine-1-phosphate receptor 2(S1PR2),and cirrhosis in conjunction with the phrase hepatic encephalopathy and portosystemic encephalopathy.PubMed,as well as Google Scholar,was the search engines used to find relevant publications.