Bile Acid Signaling Is Involved in the Neurological Decline in a Murine Model of Acute Liver Failure

McMillin, Matthew; Frampton, Gabriel; Quinn, Matthew; Ashfaq, Samir; Santos, Mario de los; Grant, Stephanie; DeMorrow, Sharon

doi:10.1016/j.ajpath.2015.10.005

Cited by 86 publications

(131 citation statements)

References 57 publications

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“…Recently, we published a report that bile acids are elevated in the cortex of AOM-treated mice, and the use of cholestyramine (to promote fecal excretion of bile acids) or Cyp7A1-null mice (that have reduced bile acid synthesis) were protected from neurological decline [26]. This is not unique to this model as BDL rats 3 weeks after surgery have signiicant elevations of lithocholic acid in the brain [62].…”

Section: Pre-clinical Therapies Targeting Inlammationmentioning

confidence: 98%

“…Increased serum bile acids have been implicated in the increased blood-brain barrier permeability observed in a rat model of chronic liver disease [28] hereby allowing access of bile acids and other signaling molecules to the brain. Furthermore, increased bile acid content in brain tissue has been demonstrated in rodent models of both acute and chronic liver diseases [26,27]. In the AOM mouse model of Type A HE, increased total bile acid content was observed in the frontal cortex, and strategies to reduced circulating bile acids (e.g., cholestyramine feeding or the use of a genetically modiied mouse with impaired bile acid synthesis) proved neuroprotective [26].…”

Section: Bile Acidsmentioning

confidence: 99%

“…It is well accepted that increased serum bile acids can be an indication of liver damage [23] and have been observed in the cerebrospinal luid of patients with fulminant hepatic failure [24], and with liver cirrhosis [25], however, their contribution to the pathogenesis of HE has only recently been suggested [26,27]. Increased serum bile acids have been implicated in the increased blood-brain barrier permeability observed in a rat model of chronic liver disease [28] hereby allowing access of bile acids and other signaling molecules to the brain.…”

Section: Bile Acidsmentioning

confidence: 99%

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Neuroinflammatory Signals during Acute and Chronic Liver Diseases

McMillin¹,

DeMorrow²

2017

Mechanisms of Neuroinflammation

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A spectrum of neurological complications can result from acute and chronic liver diseases and is termed hepatic encephalopathy. The precise pathogenic mechanisms by which hepatic encephalopathy occurs is unclear. However, it is commonly accepted that the development of hepatic encephalopathy shares a long-standing relationship with neuroinlammation. This chapter will outline the evidence for a role of neuroinlammation and proinlammatory cytokines in the pathogenesis of hepatic encephalopathy. Furthermore, we will identify the possible circulating factors, released from the liver after damage, that may contribute to the neurological complications of hepatic encephalopathy, including neuroinlammation. Lastly, we discuss the current and experimental treatment options aimed at reducing neuroinlammation for the management of hepatic encephalopathy.

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Section: Pre-clinical Therapies Targeting Inlammationmentioning

confidence: 98%

Section: Bile Acidsmentioning

confidence: 99%

Section: Bile Acidsmentioning

confidence: 99%

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Neuroinflammatory Signals during Acute and Chronic Liver Diseases

McMillin¹,

DeMorrow²

2017

Mechanisms of Neuroinflammation

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“…The bile acid system may represent another hepatic system that is altered following a TBI32. In humans and mice, bile acids are predominantly synthesized in the liver and stored in the gall bladder (rats lack a gall bladder, but have an intestinal modification to serve similar functions).…”

mentioning

confidence: 99%

“…Blood brain barrier (BBB) breakdown can facilitate bile acid entry into the brain38. Once in the brain, bile acids can be beneficial39 or detrimental3238 depending on the physiological conditions, as well as the type and location of the receptors to which they bind40. Bile acids receptors may be cell-surface or nuclear, and have tissue-specific effects related to cholesterol synthesis, bile acid synthesis, and other g-protein mediated effects4142.…”

mentioning

confidence: 99%

Hepatic alterations are accompanied by changes to bile acid transporter-expressing neurons in the hypothalamus after traumatic brain injury

Nizamutdinov

DeMorrow

McMillin

et al. 2017

Sci Rep

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Annually, there are over 2 million incidents of traumatic brain injury (TBI) and treatment options are non-existent. While many TBI studies have focused on the brain, peripheral contributions involving the digestive and immune systems are emerging as factors involved in the various symptomology associated with TBI. We hypothesized that TBI would alter hepatic function, including bile acid system machinery in the liver and brain. The results show activation of the hepatic acute phase response by 2 hours after TBI, hepatic inflammation by 6 hours after TBI and a decrease in hepatic transcription factors, Gli 1, Gli 2, Gli 3 at 2 and 24 hrs after TBI. Bile acid receptors and transporters were decreased as early as 2 hrs after TBI until at least 24 hrs after TBI. Quantification of bile acid transporter, ASBT-expressing neurons in the hypothalamus, revealed a significant decrease following TBI. These results are the first to show such changes following a TBI, and are compatible with previous studies of the bile acid system in stroke models. The data support the emerging idea of a systemic influence to neurological disorders and point to the need for future studies to better define specific mechanisms of action.

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Identification of functional farnesoid X receptors in brain neurons

Huang

Wang

et al. 2016

FEBS Letters

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Farnesoid X receptor (FXR) has been confirmed to sense bile acids in various tissues. However, its expression in brain neurons remains obscure. In this study, we identified FXR mRNA and protein expression in mouse brain neurons and in mouse/human brain tissues. FXR was predominantly localized in the nucleus in cultured neurons, but in neurons in vivo, it mainly appeared in the cytoplasm. In nuclear compartments, the neuronal FXR exhibited a punctate distribution. Activation of FXR increased the small heterodimer partner (SHP) mRNA and protein expression levels in cultured neurons and in brain tissues. These findings will help explore new functions of FXR in the brain.

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Bile Acid Signaling Is Involved in the Neurological Decline in a Murine Model of Acute Liver Failure

Cited by 86 publications

References 57 publications

Neuroinflammatory Signals during Acute and Chronic Liver Diseases

Neuroinflammatory Signals during Acute and Chronic Liver Diseases

Hepatic alterations are accompanied by changes to bile acid transporter-expressing neurons in the hypothalamus after traumatic brain injury

Identification of functional farnesoid X receptors in brain neurons

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