Bile acids activate fibroblast growth factor 19 signaling in human hepatocytes to inhibit cholesterol 7α-hydroxylase gene expression

Song, Kwang Hoon; Li, Tiangang; Owsley, Erika; Strom, Stephen C.; Chiang, John Y.L.

doi:10.1002/hep.22627

Cited by 343 publications

(327 citation statements)

References 39 publications

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“…There are many potential mechanisms by which PKC␤ either indirectly or directly can affect hepatic CYP7A1 transcription. First, p42/44 MAPK activation has been linked with CYP7A1 suppression by both SHP-dependent and SHP-independent pathways (44,45). One such study has shown that p42/44 MAPK -induced phosphorylation of hepatic SHP at serine 26 stabilizes this protein by inhibiting ubiquitin-proteasomal degradation (45).…”

Section: Discussionmentioning

confidence: 99%

“…First, p42/44 MAPK activation has been linked with CYP7A1 suppression by both SHP-dependent and SHP-independent pathways (44,45). One such study has shown that p42/44 MAPK -induced phosphorylation of hepatic SHP at serine 26 stabilizes this protein by inhibiting ubiquitin-proteasomal degradation (45). However, lack of a significant change in hepatic SHP content between genotypes argues against involvement of SHP-dependent pathways in CYP7A1 repression.…”

Section: Discussionmentioning

confidence: 99%

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Disruption of the Murine Protein Kinase Cβ Gene Promotes Gallstone Formation and Alters Biliary Lipid and Hepatic Cholesterol Metabolism

Huang¹,

Bansode

Rowland

et al. 2011

Journal of Biological Chemistry

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The protein kinase C (PKC) family of Ca 2؉ and/or lipid-activated serine-threonine protein kinases is implicated in the pathogenesis of obesity and insulin resistance. We recently reported that protein kinase C␤ (PKC␤), a calcium-, diacylglycerol-, and phospholipid-dependent kinase, is critical for maintaining whole body triglyceride homeostasis. We now report that PKC␤ deficiency has profound effects on murine hepatic cholesterol metabolism, including hypersensitivity to diet-induced gallstone formation. The incidence of gallstones increased from 9% in control mice to 95% in PKC␤ ؊/؊ mice. Gallstone formation in the mutant mice was accompanied by hyposecretion of bile acids with no alteration in fecal bile acid excretion, increased biliary cholesterol saturation and hydrophobicity indices, as well as hepatic p42/44 MAPK activation, all of which enhance susceptibility to gallstone formation. Lithogenic diet-fed PKC␤ ؊/؊ mice also displayed decreased expression of hepatic cholesterol-7␣-hydroxylase (CYP7A1) and sterol 12␣-hydroxylase (CYP8b1). Finally, feeding a modified lithogenic diet supplemented with milk fat, instead of cocoa butter, both increased the severity of and shortened the interval for gallstone formation in PKC␤ ؊/؊ mice and was associated with dramatic increases in cholesterol saturation and hydrophobicity indices. Taken together, the findings reveal a hitherto unrecognized role of PKC␤ in fine tuning diet-induced cholesterol and bile acid homeostasis, thus identifying PKC␤ as a major physiological regulator of both triglyceride and cholesterol homeostasis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Disruption of the Murine Protein Kinase Cβ Gene Promotes Gallstone Formation and Alters Biliary Lipid and Hepatic Cholesterol Metabolism

Huang¹,

Bansode

Rowland

et al. 2011

Journal of Biological Chemistry

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“…Fgf15/FGF19 is an endocrine-acting factor that is released in the portal circulation. Binding of Fgf15/FGF19 to its hepatic receptor (complex of Fgfr4 and bKlotho) results in activation of a signaling cascade that causes downregulation of Cyp7a1 and diminished bile salt synthesis [42][43][44] (Fig. 1).…”

Section: Farnesoid X Receptor and Liver Regenerationmentioning

confidence: 99%

The role of bile salts in liver regeneration

et al. 2016

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A growing body of evidence has demonstrated that bile salts are important for liver regeneration following partial hepatectomy. The relative bile salt overload after partial liver resection causes activation of bile salt receptors in non-parenchymal (viz. the plasma membrane receptor TGR5) and parenchymal (viz. the intracellular receptor FXR) cells in the liver, thus, providing signals to the regenerative process. Impaired bile salt signaling in mice with genetic deficiency of Tgr5 or Fxr results in delayed liver regeneration after partial hepatectomy, and is accompanied by mortality in case of Fxr knock-out mice. Conversely, compensatory liver re-growth in hepatectomized mice can be stimulated by feeding of bile salts or alisol B 23-acetate, a natural triterpenoid agonist of Fxr. A large number of animal studies underscore the importance of strict maintenance of bile salt homeostasis for proper progression of liver regeneration. Both ileal and hepatic Fxr play a key role in regulation of bile salt homeostasis and, thus, preventing hepatotoxicity caused by excessive levels of bile salts. They further contribute to liver regeneration by induction of mitogenic factors. Agents that target bile salt receptors hold promise as drugs to stimulate liver regeneration in selected patients.

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“…FGF19 has recently been shown to be present in the human hepatocyte [38], and it is not known whether patients with idiopathic bile acid malabsorption form FGF19 in the liver. We might dare to predict that there are other patients with idiopathic bile acid malabsorption who will prove to be deficient in FGF receptor 4 or do not form the required cofactor, b-klotho.…”

Section: Editorialmentioning

confidence: 99%

Chronic diarrhea caused by idiopathic bile acid malabsorption: an explanation at last

Hofmann¹

2009

Expert Review of Gastroenterology & Hepatology

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Bile acids activate fibroblast growth factor 19 signaling in human hepatocytes to inhibit cholesterol 7α-hydroxylase gene expression

Cited by 343 publications

References 39 publications

Disruption of the Murine Protein Kinase Cβ Gene Promotes Gallstone Formation and Alters Biliary Lipid and Hepatic Cholesterol Metabolism

Disruption of the Murine Protein Kinase Cβ Gene Promotes Gallstone Formation and Alters Biliary Lipid and Hepatic Cholesterol Metabolism

The role of bile salts in liver regeneration

Chronic diarrhea caused by idiopathic bile acid malabsorption: an explanation at last

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