scholarly journals Role of cholesterol synthesis in regulation of bile acid synthesis and biliary cholesterol secretion in humans.

1991 ◽  
Vol 32 (7) ◽  
pp. 1143-1149
Author(s):  
JC Mitchell ◽  
BG Stone ◽  
GM Logan ◽  
WC Duane
Keyword(s):  
Bile Acid ◽  
Cholesterol Synthesis ◽  
Acid Synthesis ◽  
Bile Acid Synthesis ◽  
Biliary Cholesterol ◽  
Biliary Cholesterol Secretion ◽  
Cholesterol Secretion

Relationship between Hepatic Cholesterol Synthesis and Biliary Cholesterol Secretion in Man: Hepatic Cholesterol Synthesis is not a Major Regulator of Biliary Lipid Secretion

1982 ◽  
Vol 62 (5) ◽  
pp. 515-519 ◽  
Author(s):  
P. N. Maton ◽  
A. Reuben ◽  
R. H. Dowling
Keyword(s):  
Bile Acid ◽  
Cholesterol Synthesis ◽  
Acid Output ◽  
Hepatic Cholesterol ◽  
Biliary Cholesterol ◽  
Lipid Secretion ◽  
Hepatic Cholesterol Synthesis ◽  
Biliary Cholesterol Secretion ◽  
Cholesterol Secretion

1. To examine the role of newly synthesized cholesterol as a determinant of bile lipid secretion, both hepatic cholesterol synthesis (as judged by the activity of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, EC 1.1.1.34; HMGCoAR) and steady state biliary cholesterol output were measured in nine patients. 2. HMGCoAR levels varied four fold (9–40 pmol min−1 mg−1) and biliary cholesterol secretion 2–5-fold (0.60−1.15 μUmol h−1 kg−1) but there was no correlation between these two variables (r = 0.18; P>0.05) nor between biliary bile acid output and HMGCoAR activity (r = 0.34; P>0.05). 3. There was, however, a linear relationship between bile acid and phospholipid secretion (r = 0.77; P<0.001) and between bile acid and cholesterol secretion (r = 0.69; P<0.05). 4. These results suggest that HMGCoAR activity is not a major determinant of cholesterol secretion nor at these secretion rates is HMGCoAR activity related to bile acid return to the liver.

Abstract 629: FGF15/19 Upregulates Hepatic ABCG5 and ABCG8 to Promote Biliary Cholesterol Secretion

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Sonja Pijut ◽  
Yuhuan Wang ◽  
Lisa Bennett ◽  
Richard Lee ◽  
Gregory Graf
Keyword(s):  
Body Weight ◽  
Bile Acid ◽  
Protein Expression ◽  
Cholesterol Metabolism ◽  
Acid Synthesis ◽  
Bile Acid Synthesis ◽  
Wild Type ◽  
Biliary Cholesterol ◽  
Biliary Cholesterol Secretion ◽  
Cholesterol Secretion

Background: Elevated hepatic cholesterol is thought to contribute to the development of nonalcoholic fatty liver disease, a condition highly associated with cardiovascular risk factors. The ABCG5 and ABCG8 (G5G8) heterodimer is responsible for up to 90% of biliary cholesterol secretion and is a potential therapeutic target for promoting cholesterol elimination. We have previously demonstrated that ursodiol (UDCA), a pharmacologic bile acid, increases G5G8 protein expression and biliary cholesterol secretion. However, whole body cholesterol elimination is minimized likely due to simultaneous suppression of bile acid synthesis through upregulation of FGF15/19. The objectives of this study are to determine whether FGF15/19 regulates G5G8 and determine whether UDCA requires FGF15/19 signaling in order to upregulate G5G8. Methods: Mice were injected with two doses of FGF19 or carrier (PBS) 1μg/g body weight within an 8-hour treatment window. A separate group of wild type (WT) and G5G8 knockout (KO) mice were similarly injected with FGF19. In another experiment, WT mice were fed chow or UDCA-supplemented diet in the absence or presence of FGF15/19 signaling inhibition which was achieved by FGFR4 antisense oligonucleotide (ASO) supplied by Ionis Pharmaceuticals. In all experiments, body weight, liver weight, bile flow rate and plasma, hepatic and biliary lipids were measured. Immunoblotting of G5G8 and real-time PCR of genes involved in cholesterol metabolism were also conducted. Results: Mice injected with FGF19 had increased biliary lipids (PBS: 5.287±0.5720, FGF19: 8.098±0.6114, n=6), decreased Cyp7a1 (PBS: 1.021±0.1064 FGF19: 0.07787±0.01345 n=5-7) and Cyp8b1 (PBS: 1.018±0.09846, FGF19: 0.2647±0.05609, n=5-7) expression, and increased G5G8 protein expression compared to mice injected with PBS. In G5G8 KO mice injected with FGF19, there was only a small increase in plasma free cholesterol (WT: 51.96±2.098, KO: 62.24±2.562, n=4) and no other significant changes in cholesterol metabolism compared to wild type mice injected with FGF19. Conclusion: In conclusion, FGF15/19 suppresses bile acid synthesis and post-transcriptionally upregulates G5G8. However, in the absence of G5G8, FGF15/19 did not disrupt cholesterol metabolism.

Abstract 131: Restoration of ER Stress and Induction of FGF15/19 Independently Rescue ABCG5 ABCG8 Sterol Transporter

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Yuhuan Wang ◽  
Kai Su ◽  
Nadezhda Sabeva ◽  
Ailing Ji ◽  
Deneys van der Westhuyzen ◽  
...  
Keyword(s):  
Bile Acid ◽  
Er Stress ◽  
Acid Synthesis ◽  
Bile Acid Synthesis ◽  
Biliary Cholesterol ◽  
Leptin Receptors ◽  
Insulin Resistant ◽  
Protein Levels ◽  
The Face ◽  
Biliary Cholesterol Secretion

Mice lacking leptin (ob/ob) or its receptor (db/db) are obese, insulin resistant and have reduced levels of biliary cholesterol due, in part, to reduced levels of hepatic ABCG5 ABCG8 (G5G8). Chronic leptin replacement restores G5G8 abundance and increases biliary cholesterol concentrations, but the molecular mechanism responsible for G5G8 regulation remains unclear. In the current study, we conducted a series of experiments to address potential mechanisms. To determine if leptin signaling directly regulates hepatic G5G8 abundance, we acutely replaced leptin in ob/ob mice and deleted hepatic leptin receptors in lean mice. Neither manipulation altered G5G8 abundance or biliary cholesterol. Similarly, hepatic vagotomy had no effect on G5G8. Alternatively, the G5G8 protein complex may be decreased due to compromised ER stress. It has been previously reported that tauroursodeoxycholate (TUDCA) alleviates ER stress. It also increases G5G8 and biliary cholesterol in both lean and db/db mice. The ER chaperone protein, glucose regulated protein 78-kDa (GRP78) can restore ER function and reduce unfolded protein response (UPR) signaling. Therefore, we tested the hypothesis that expression of GRP78 could rescue G5G8 in db/db mice. Adenovirus encoding GRP78 was administered to db/db mice and the effect on hepatic G5G8 was determined. G5 and G8 proteins and biliary cholesterol were increased in the absence of changes in mRNAs encoding either protein. However, TUDCA has also been shown to induce FGF15. In several models of bile acid feeding, FGF15/19 is stimulated in ileum and activates its receptor in liver to repress bile acid synthesis. Simultaneously, G5G8 and biliary cholesterol secretion are elevated. To determine if FGF15/19 had a direct effect on hepatic G5G8, we injected C57BL/6 mice with recombinant FGF19. CYP7A1 and CYP8B1 mRNA expression were both strongly suppressed, whereas G5G8 increased at both mRNA and protein levels. In conclusion, G5G8 can be rescued in ob/ob and db/db mice through multiple mechanisms that include restoration of ER functions and FGF15/19 signaling. Counter regulation of CYP7A1, CYP8B1, and G5G8 by FGF15/19 allows for the maintenance of hepatic sterol elimination in the face of expanded bile acid pool.

scholarly journals Recombinant 2-enoyl-CoA hydratase derived from rat peroxisomal multifunctional enzyme 2: role of the hydratase reaction in bile acid synthesis

1997 ◽  
Vol 328 (2) ◽  
pp. 377-382 ◽  
Author(s):  
Yong-Mei QIN ◽  
M. Antti HAAPALAINEN ◽  
Demara CONRY ◽  
A. Dean CUEBAS ◽  
J. Kalervo HILTUNEN ◽  
...  
Keyword(s):  
Bile Acid ◽  
Acid Synthesis ◽  
Bile Acid Synthesis ◽  
Hydration Reaction ◽  
Multifunctional Enzymes ◽  
Hydratase Activity ◽  
Hydroxyacyl Coa Dehydrogenase ◽  
Liver Peroxisomes ◽  
Enoyl Coa Hydratase

Rat liver peroxisomes contain two multifunctional enzymes: (1) perMFE-1 [2-enoyl-CoA hydratase 1/Δ3,Δ2-enoyl-CoA isomerase/(S)-3-hydroxyacyl-CoA dehydrogenase] and (2) perMFE-2 [2-enoyl-CoA hydratase 2/(R)-3-hydroxyacyl-CoA dehydrogenase]. To investigate the role of the hydratase activity of perMFE-2 in β-oxidation, a truncated version of perMFE-2 was expressed in Escherichia coli as a recombinant protein. The protein catalyses the hydration of straight-chain (2E)-enoyl-CoAs to (3R)-hydroxyacyl-CoAs, but it is devoid of hydratase 1 [(2E)-enoyl-CoA to (3S)-hydroxyacyl-CoA] and (3R)-hydroxyacyl-CoA dehydrogenase activities. The purified enzyme (46 kDa hydratase 2) can be stored as an active enzyme for at least half a year. The recombinant enzyme hydrates (24E)-3α,7α,12α-trihydroxy- 5β-cholest-24-enoyl-CoA to (24R,25R)-3α,7α,12α,24-tetrahydroxy-5β-cholestanoyl-CoA, which has previously been characterized as a physiological intermediate in bile acid synthesis. The stereochemistry of the products indicates that the hydration reaction catalysed by the enzyme proceeds via a syn mechanism. A monofunctional 2-enoyl-CoA hydratase 2 has not been observed as a wild-type protein. The recombinant 46 kDa hydratase 2 described here survives in a purified form under storage, thus being the first protein of this type amenable to application as a tool in metabolic studies.

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