Mutations in the nuclear bile acid receptor FXR cause progressive familial intrahepatic cholestasis

Gomez‐Ospina, Natalia; Potter, Carol; Xiao, Rui; Manickam, Kandamurugu; Kim, Mi Sun; Kim, Kang Ho; Shneider, Benjamin L.; Picarsic, Jennifer; Jacobson, Theodora A.; Zhang, Jing; He, Weimin; Liu, Peng Fei; Knisely, Alexander S.; Finegold, Milton J.; Muzny, Donna M.; Boerwinkle, Eric; Lupski, James R.; Plon, Sharon E.; Gibbs, Richard A.; Eng, Christine M.; Yang, Yaping; Washington, Gabriel C.; Porteus, Matthew H.; Berquist, William E.; Kambham, Neeraja; Singh, Ravinder J.; Xia, Fan; Enns, Gregory M.; Moore, David D.

doi:10.1038/ncomms10713

Cited by 251 publications

(200 citation statements)

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“…Four distinct observations led us to conclude that this was due to a direct activation of the complement and coagulation by FXR. In the first, we confirmed an earlier study indicating that GW4064 induces expression of fibrinogens in a human hepatocyte cell line, and extended it to several other components of the complement and coagulation pathways [35] . In the second, we noted that the results of genome-wide binding studies for FXR in mouse and human hepatocytes identified the complement and coagulation pathway as third on the list of targeted pathways [36] .…”

Section: Do Fxr and Pparα Regulate Secretion?supporting

confidence: 77%

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Regulation of Liver Energy Balance by the Nuclear Receptors Farnesoid X Receptor and Peroxisome Proliferator Activated Receptor α

Kim

Moore²

2017

Dig Dis

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Background: The liver undergoes major changes in substrate utilization and metabolic output over the daily feeding and fasting cycle. These changes occur acutely in response to hormones such as insulin and glucagon, with rapid changes in signaling pathways mediated by protein phosphorylation and other post-translational modifications. They are also reflected in chronic alterations in gene expression in response to nutrient-sensitive transcription factors. Among these, the nuclear receptors farnesoid X receptor (FXR) and peroxisome proliferator activated receptor α (PPARα) provide an intriguing, coordinated response to maintain energy balance in the liver. FXR is activated in the fed state by bile acids returning to the liver, while PPARα is activated in the fasted state in response to the free fatty acids produced by adipocyte lipolysis or possibly other signals. Key Messages: Previous studies indicate that FXR and PPARα have opposing effects on each other's primary targets in key metabolic pathways including gluconeogenesis. Our more recent work shows that these 2 nuclear receptors coordinately regulate autophagy: FXR suppresses this pathway of nutrient and energy recovery, while PPARα activates it. Another recent study indicates that FXR activates the complement and coagulation pathway, while earlier studies identify this as a negative target of PPARα. Since secretion is a very energy- and nutrient-intensive process for hepatocytes, it is possible that FXR licenses it in the nutrient-rich fed state, while PPARα represses it to spare resources in the fasted state. Energy balance is a potential connection linking FXR and PPARα regulation of autophagy and secretion, 2 seemingly unrelated aspects of hepatocyte function. Conclusions: FXR and PPARα act coordinately to promote energy balance and homeostasis in the liver by regulating autophagy and potentially protein secretion. It is quite likely that their impact extends to additional pathways relevant to hepatic energy balance, and that these pathways will in turn interface with other well-known nutrient-responsive mechanisms of energy control.

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Section: Do Fxr and Pparα Regulate Secretion?supporting

confidence: 77%

“…We identified 4 patients from 2 families with loss of function mutations in the Kim NR1H4 gene, which encodes FXR [35] . These patients all exhibited severe neonatal cholestasis, with 2 in one family surviving after liver transplants and the other 2 dying prior to a year of age.…”

Section: Do Fxr and Pparα Regulate Secretion?mentioning

confidence: 99%

Regulation of Liver Energy Balance by the Nuclear Receptors Farnesoid X Receptor and Peroxisome Proliferator Activated Receptor α

Kim

Moore²

2017

Dig Dis

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“…Hereditary cholestasis with conjugated hyperbilirubinemia in children presents as a range of disorders, from transient neonatal cholestasis (TNC) through benign recurrent intrahepatic cholestasis (BRIC) to progressive familial intrahepatic cholestasis (PFIC) . Of children with such cholestasis and low or normal serum gamma‐glutamyltransferase (GGT) activity (GGT <100 IU/L; “low‐GGT cholestasis”), two thirds carry either ATP8B1 or ABCB11 mutations; the remaining instances of childhood cholestasis with conjugated hyperbilirubinemia and low GGT can sometimes be attributed to mutations in TJP2 , which encodes tight junction protein 2 (TJP2); in genes involved in bile acid synthesis, including HSD3B7 , AKR1D1 , CYP7B1 , AMACR , and CYP27A1 ; in VPS33B and VIPAS39 , which cause arthrogryposis‐renal dysfunction‐cholestasis (ARC) syndrome; and in NR1H4 , encoding the nuclear farnesoid X receptor (FXR) (see http://onlinelibrary.wiley.com/doi/10.1002/hep.29020/suppinfo). However, approximately one fifth of such patients remain without an identified genetic defect, suggesting that mutations at additional loci are responsible for childhood low‐GGT cholestasis.…”

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confidence: 99%

Defects in myosin VB are associated with a spectrum of previously undiagnosed low γ‐glutamyltransferase cholestasis

et al. 2017

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Hereditary cholestasis in childhood and infancy with normal serum gamma‐glutamyltransferase (GGT) activity is linked to several genes. Many patients, however, remain genetically undiagnosed. Defects in myosin VB (MYO5B; encoded by MYO5B) cause microvillus inclusion disease (MVID; MIM251850) with recurrent watery diarrhea. Cholestasis, reported as an atypical presentation in MVID, has been considered a side effect of parenteral alimentation. Here, however, we report on 10 patients who experienced cholestasis associated with biallelic, or suspected biallelic, mutations in MYO5B and who had neither recurrent diarrhea nor received parenteral alimentation. Seven of them are from two study cohorts, together comprising 31 undiagnosed low‐GGT cholestasis patients; 3 are sporadic. Cholestasis in 2 patients was progressive, in 3 recurrent, in 2 transient, and in 3 uncategorized because of insufficient follow‐up. Liver biopsy specimens revealed giant‐cell change of hepatocytes and intralobular cholestasis with abnormal distribution of bile salt export pump (BSEP) at canaliculi, as well as coarse granular dislocation of MYO5B. Mass spectrometry of plasma demonstrated increased total bile acids, primary bile acids, and conjugated bile acids, with decreased free bile acids, similar to changes in BSEP‐deficient patients. Literature review revealed that patients with biallelic mutations predicted to eliminate MYO5B expression were more frequent in typical MVID than in isolated‐cholestasis patients (11 of 38 vs. 0 of 13). Conclusion: MYO5B deficiency may underlie 20% of previously undiagnosed low‐GGT cholestasis. MYO5B deficiency appears to impair targeting of BSEP to the canalicular membrane with hampered bile acid excretion, resulting in a spectrum of cholestasis without diarrhea. (Hepatology 2017;65:1655‐1669).

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“…FXR is known to tightly regulate bile acid, glucose and fat homeostasis through the gut-liver axis to ensure efficient functioning of both organs. Indeed, infants with mutations in FXR develop NASH and NAFLD with lipid deposition and bile acid accumulation [53] .…”

Section: Short Bowel Syndromementioning

confidence: 99%

Disease-Associated Changes in Bile Acid Profiles and Links to Altered Gut Microbiota

Joyce

Gahan²

2017

Dig Dis

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The gastrointestinal microbiota plays a central role in the host metabolism of bile acids through deconjugation and dehydroxylation reactions, which generate unconjugated free bile acids and secondary bile acids respectively. These microbially generated bile acids are particularly potent signalling molecules that interact with host bile acid receptors (including the farnesoid X receptor, vitamin D receptor and TGR5 receptor) to trigger cellular responses that play essential roles in host lipid metabolism, electrolyte transport and immune regulation. Perturbations of microbial populations in the gut can therefore profoundly alter bile acid profiles in the host to impact upon the digestive and signalling properties of bile acids in the human superorganism. A number of recent studies have clearly demonstrated the occurrence of microbial disturbances allied to alterations in host bile acid profiles that occur across a range of disease states. Intestinal diseases including irritable bowel syndrome, inflammatory bowel disease (IBD), short bowel syndrome and Clostridium difficile infection all exhibit concurrent alterations in the composition of the gut microbiota and changes to host bile acid profiles. Similarly, extraintestinal diseases and syndromes such as asthma and obesity may be linked to aberrant bile acid profiles in the host. Here, we focus upon recent studies that highlight the links between alterations to gut microbial communities and altered bile acid profiles across a range of diseases from asthma to IBD.

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Mutations in the nuclear bile acid receptor FXR cause progressive familial intrahepatic cholestasis

Cited by 251 publications

References 43 publications

Regulation of Liver Energy Balance by the Nuclear Receptors Farnesoid X Receptor and Peroxisome Proliferator Activated Receptor α

Regulation of Liver Energy Balance by the Nuclear Receptors Farnesoid X Receptor and Peroxisome Proliferator Activated Receptor α

Defects in myosin VB are associated with a spectrum of previously undiagnosed low γ‐glutamyltransferase cholestasis

Disease-Associated Changes in Bile Acid Profiles and Links to Altered Gut Microbiota

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