Farnesoid X Receptor Activation Promotes Hepatic Amino Acid Catabolism and Ammonium Clearance in Mice

Massafra, Vittoria; Milona, Alexandra; Vos, Harmjan R.; Ramos, Rúben J.; Gerrits, Johan; Willemsen, Ellen C.L.; Pittol, José M. Ramos; Ijssennagger, Noortje; Houweling, Martin; Prinsen, Hubertus C.M.T.; Verhoeven‐Duif, Nanda M.; Burgering, Boudewijn M.T.; Mil, Saskia W.C. van

doi:10.1053/j.gastro.2017.01.014

Cited by 53 publications

(38 citation statements)

References 45 publications

(37 reference statements)

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“…Clearly, precise identification of particular signaling pathway needs further study. Taking into account that the use of specific FXR agonist is suggested as a promising therapy in a broad spectrum of diseases, including hepatic failure, metabolic syndrome, diabetes, obesity, or vascular impairment occurring in liver cirrhosis [ 16 , 44 , 45 , 46 ], our data contribute to the idea that strengthening of FXR/SHP signaling may be beneficial in the treatment of the ALF.…”

Section: Discussionmentioning

confidence: 78%

“…There is a growing consensus that both the feedback regulation of BA synthesis and metabolic control by BA of numerous intracellular metabolic pathways are coordinated by the activity of the farnesoid X receptor (FXR), a member of the nuclear receptor superfamily. After BA binding to FXR, it induces the expression of small heterodimer partner (SHP) [ 15 , 16 ]. FXR regulates transcription of genes involved in BA synthesis, absorption, uptake, and transport maintaining BA homeostasis [ 12 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

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The Status of Bile Acids and Farnesoid X Receptor in Brain and Liver of Rats with Thioacetamide-Induced Acute Liver Failure

Czarnecka

Milewski

2020

IJMS

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Acute liver failure (ALF) leads to neurological symptoms defined as hepatic encephalopathy (HE). Although accumulation of ammonia and neuroinflammation are generally accepted as main contributors to HE pathomechanism, a buildup of bile acids (BA) in the blood is a frequent component of liver injury in HE patients. Recent studies have identified the nuclear farnesoid X receptor (FXR) acting via small heterodimer partner (SHP) as a mediator of BA-induced effects in the brain of ALF animals. The present study investigated the status of the BA–FXR axis in the brain and the liver, including selective changes in pertinent genes in thioacetamide (TAA)-induced ALF in Sprague–Dawley rats. FXR was found in rat neurons, confirming earlier reports for mouse and human brain. BA accumulated in blood but not in the brain tissue. Expression of mRNAs coding for Fxr and Shp was reduced in the hippocampus and of Fxr mRNA also in the cerebellum. Changes in Fxr mRNA levels were not followed by changes in FXR protein. The results leave open the possibility that mobilization of the BA–FXR axis in the brain may not be necessarily pathognomonic to HE but may depend upon ALF-related confounding factors.

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Section: Discussionmentioning

confidence: 78%

Section: Introductionmentioning

confidence: 99%

The Status of Bile Acids and Farnesoid X Receptor in Brain and Liver of Rats with Thioacetamide-Induced Acute Liver Failure

Czarnecka

Milewski

2020

IJMS

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“…Cancer cells suppress urea cycle and patients with urea cycle enzyme deficiencies have a 200x greater HCC incidence, highlighting the importance of this pathway in hepatic tumorigenesis (36)(37)(38). Moreover, recent data revealed that BAs promote amino acid catabolism (31), which substantiate that BAs act as a central node in liver cancer development.…”

Section: Discussionmentioning

confidence: 94%

“…BAs have recently been shown to promote ureagenesis in an FXRdependent manner (31). Intriguingly, DKO mice have high BAs, however, they lack FXR.…”

Section: Sex-specific Metabolic Programs Regulate Tumorigenesismentioning

confidence: 99%

Sex differences in bile acid homeostasis and excretion underlie the disparity in liver cancer incidence between males and females

Patton

Kelekar

Taylor

et al. 2020

Preprint

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Hepatocellular carcinoma (HCC) is the most common liver cancer with a higher incidence in males. Here, we report that the spontaneous HCC development subsequent to the deletion of both Farnesoid X Receptor and Small Heterodimer Partner (DKO) mimics the sex-specific incidence seen clinically. In female DKO mice, we find lower levels of circulating bile acids (BA) and show that BAs can co-opt the estrogen axis to auto-regulate their homeostasis and amino acid metabolism. These regulations are lost when female mice are ovariectomized.Conversely, increasing serum BA levels is sufficient to promote tumorigenesis in female livers. To examine the translational relevance, we mined the transcriptomic signatures corresponding to that of female mice and found that it correlated well with those of low-grade tumors and associated with better outcomes for HCC patients. We demonstrate that decreasing enterohepatic recirculation of BAs using a resin dramatically reduced the liver cancer burden in male mice. These results uncover that sexual dimorphism in liver cancer incidence is linked to sex-differences in the handling of circulating BA concentrations and that lowering it might alleviate liver cancer. SignificanceWe demonstrate that serum BA concentration facilitates sex-differences in tumor burden, with reduced BA levels resulting in lower HCC risk in female mice.Increasing or decreasing circulating BA levels, promotes or alleviates HCC risk, respectively. We show that the sex-specific gene profiles identified in the DKO mice model of HCC correlate directly with patient outcomes.

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“…In addition, OCA administration reduces liver transaminases, IFN-gamma and TNF- in an autoimmune hepatitis mouse model [108]. FXR activation has been shown to promote hepatic amino acid catabolism and ammonium clearance via ureagenesis and glutamine synthesis [109]. OCA also decreases intestinal infl ammation in various colitis animal models [110].…”

Section: Role Of Fxr Agonist In Nafld Treatmentmentioning

confidence: 99%

Farnesoid X Receptor Agonist as a new treatment option for Non-Alcoholic Fatty Liver disease: A Review

Singh¹,

Kharbanda²

2017

Arch Hepat Res

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Farnesoid X Receptor Activation Promotes Hepatic Amino Acid Catabolism and Ammonium Clearance in Mice

Cited by 53 publications

References 45 publications

The Status of Bile Acids and Farnesoid X Receptor in Brain and Liver of Rats with Thioacetamide-Induced Acute Liver Failure

The Status of Bile Acids and Farnesoid X Receptor in Brain and Liver of Rats with Thioacetamide-Induced Acute Liver Failure

Sex differences in bile acid homeostasis and excretion underlie the disparity in liver cancer incidence between males and females

Farnesoid X Receptor Agonist as a new treatment option for Non-Alcoholic Fatty Liver disease: A Review

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