AhR and SHP regulate phosphatidylcholine and S-adenosylmethionine levels in the one-carbon cycle

Kim, Young Chae; Seok, Sunmi; Byun, Sangwon; Kong, Bo; Zhang, Yang; Guo, Grace L.; Xie, Wen; Ma, Jian; Kemper, Byron; Kemper, Jongsook Kim

doi:10.1038/s41467-018-03060-y

Cited by 47 publications

(75 citation statements)

References 53 publications

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“…PEMT may remove PE, which is flipped to the inner canalicular membrane by ATP8B1, to offset the continuous loss of PC into bile and also produce PC locally for direct delivery to the canalicular membrane. Recent literature reports that Pemt is a BA‐responsive gene and suggests that PEMT plays an important role in maintenance of biliary secretion capacity . Thus, ultimately the decreased PC:PE ratio is likely responsible for the loss of canalicular structure and contributes to hepatic BSEP deficiency in Pemt –/– mice.…”

Section: Discussionmentioning

confidence: 99%

“…Recent literature reports that Pemt is a BA-responsive gene and suggests that PEMT plays an important role in maintenance of biliary secretion capacity. (42) Thus, ultimately the decreased PC:PE ratio is likely responsible for the loss of canalicular structure and contributes to hepatic BSEP deficiency in Pemt -/mice.…”

Section: Hepatic Changes Contributing To Cholestasis and Bsep Deficiencymentioning

confidence: 99%

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Impaired Hepatic Phosphatidylcholine Synthesis Leads to Cholestasis in Mice Challenged With a High‐Fat Diet

et al. 2019

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Phosphatidylethanolamine N‐methyltransferase (PEMT) is a hepatic integral membrane protein localized to the endoplasmic reticulum (ER). PEMT catalyzes approximately 30% of hepatic phosphatidylcholine (PC) biosynthesis. Pemt–/– mice fed a high‐fat diet (HFD) develop steatohepatitis. Interestingly, portions of the ER located close to the canaliculus are enriched in PEMT. Phospholipid balance and asymmetrical distribution by adenosine triphosphatase phospholipid transporting 8B1 (ATP8B1) on the canalicular membrane is required for membrane integrity and biliary processes. We hypothesized that PEMT is an important supplier of PC to the canaliculus and that PEMT activity is critical for the maintenance of canalicular membrane integrity and bile formation following HFD feeding when there is an increase in overall hepatic PC demand. Pemt+/+ and Pemt–/– mice were fed a chow diet, an HFD, or a choline‐supplemented HFD. Plasma and hepatic indices of liver function and parameters of bile formation were determined. Pemt–/– mice developed cholestasis, i.e, elevated plasma bile acid (BA) concentrations and decreased biliary secretion rates of BAs and PC, during HFD feeding. The maximal BA secretory rate was reduced more than 70% in HFD‐fed Pemt–/– mice. Hepatic ABCB11/bile salt export protein, responsible for BA secretion, was decreased in Pemt–/– mice and appeared to be retained intracellularly. Canalicular membranes of HFD‐fed Pemt–/– mice contained fewer invaginations and displayed a smaller surface area than Pemt+/+ mice. Choline supplementation (CS) prevented and reversed the development of HFD‐induced cholestasis. Conclusion: We propose that hepatic PC availability is critical for bile formation. Dietary CS might be a potential noninvasive therapy for a specific subset of patients with cholestasis.

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Section: Discussionmentioning

confidence: 99%

Section: Hepatic Changes Contributing To Cholestasis and Bsep Deficiencymentioning

confidence: 99%

Impaired Hepatic Phosphatidylcholine Synthesis Leads to Cholestasis in Mice Challenged With a High‐Fat Diet

et al. 2019

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“…33 PC has hepatoprotective effects and can resist liver injury caused by alcohol, drugs, and environmental pollutants. 34,35 The signicant increase in PC content might indicate that PC exerts a protective effect on liver cells against the toxic effects of CW. In a chronic pathophysiological stressed heart, a decreased triacylglycerol (TG) content can buffer potential toxic lipid intermediates in cells, and TG can also directly participate in the regulation of intracellular signaling pathways.…”

Section: Discussionmentioning

confidence: 99%

A UPLC-MS-based metabolomics approach to reveal the attenuation mechanism of Caowu compatibility with Yunnan Baiyao

et al. 2019

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Yunnan Baiyao (YNBY) is a well-known traditional Chinese medicine containing Caowu (Aconiti kusnezoffii radix, CW). However, the application of YNBY is limited by the toxicity of CW. Notably, CW is not used alone in YNBY, but is combined with other herbs in a formula for clinical use. In the present study, the compatibility of the protective effects and mechanism of YNBY with the potential toxicity of CW was investigated. After combining with other compatible herbs, the serum metabolic disorder induced by CW can be regulated. Using UPLC-MS-based metabolomics, 63 endogenous serum metabolites were identified as being associated with the potential toxicity of CW, 17 of which were regulated to normal levels when CW was combined with other compatible herbs in YNBY. These regulated metabolites were closely related to glycerophospholipid metabolism, glycosylphosphatidylinositol (GPI)-anchor biosynthesis, tyrosine metabolism, and primary bile acid biosynthesis metabolic pathways. This study aims to evaluate the attenuation mechanism of CW compatibility with YNBY.

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“…Chromatin immunoprecipitation (ChIP) and re‐ChIP assays were performed as described, with primer sequences shown in Supporting Table . Coimmunoprecipitation assays using liver whole‐cell extracts were performed as described …”

Section: Methodsmentioning

confidence: 99%

“…MLL3 (KMT2C) and its closest homolog MLL4 (KMT2D) are known epigenetic regulators of BA metabolism . SHP does not have a DNA binding domain but acts as a corepressor for numerous transcriptional factors . SHP links elevated hepatic BA levels to epigenetic repression of genes involved in BA synthesis and reuptake, including cholesterol 7α hydroxylase ( Cyp7a1 ), sterol 12α hydroxylase ( Cyp8b1 ), and sodium/taurocholate cotransporting polypeptide ( Ntcp ), by recruiting repressive histone‐modifying proteins to these genes .…”

mentioning

confidence: 99%

MicroRNA‐210 Promotes Bile Acid–Induced Cholestatic Liver Injury by Targeting Mixed‐Lineage Leukemia‐4 Methyltransferase in Mice

et al. 2020

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BaCKgRoUND aND aIMS:Bile acids (BAs) are important regulators of metabolism and energy balance, but excess BAs cause cholestatic liver injury. The histone methyltransferase mixed-lineage leukemia-4 (MLL4) is a transcriptional coactivator of the BA-sensing nuclear receptor farnesoid X receptor (FXR) and epigenetically up-regulates FXR targets important for the regulation of BA levels, small heterodimer partner (SHP), and bile salt export pump (BSEP). MLL4 expression is aberrantly down-regulated and BA homeostasis is disrupted in cholestatic mice, but the underlying mechanisms are unclear. appRoaCH aND ReSUltS: We examined whether elevated microRNA-210 (miR-210) in cholestatic liver promotes BA-induced pathology by inhibiting MLL4 expression. miR-210 was the most highly elevated miR in hepatic SHP-downregulated mice with elevated hepatic BA levels. MLL4 was identified as a direct target of miR-210, and overexpression of miR-210 inhibited MLL4 and, subsequently, BSEP and SHP expression, resulting in defective BA metabolism and hepatotoxicity with inflammation. miR-210 levels were elevated in cholestatic mouse models, and in vivo silencing of miR-210 ameliorated BA-induced liver pathology and decreased hydrophobic BA levels in an MLL4-dependent manner. In gene expression studies, SHP inhibited miR-210 expression by repressing a transcriptional activator, Kruppel-like factor-4 (KLF4). In patients with primary biliary cholangitis/ cirrhosis (PBC), hepatic levels of miR-210 and KLF4 were highly elevated, whereas nuclear levels of SHP and MLL4 were reduced. CoNClUSIoNS:Hepatic miR-210 is physiologically regulated by SHP but elevated in cholestatic mice and patients with PBC, promoting BA-induced liver injury in part by targeting MLL4. The miR-210-MLL4 axis is a potential target for the treatment of BA-associated hepatobiliary disease.

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AhR and SHP regulate phosphatidylcholine and S-adenosylmethionine levels in the one-carbon cycle

Cited by 47 publications

References 53 publications

Impaired Hepatic Phosphatidylcholine Synthesis Leads to Cholestasis in Mice Challenged With a High‐Fat Diet

Impaired Hepatic Phosphatidylcholine Synthesis Leads to Cholestasis in Mice Challenged With a High‐Fat Diet

A UPLC-MS-based metabolomics approach to reveal the attenuation mechanism of Caowu compatibility with Yunnan Baiyao

MicroRNA‐210 Promotes Bile Acid–Induced Cholestatic Liver Injury by Targeting Mixed‐Lineage Leukemia‐4 Methyltransferase in Mice

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