Bile acid synthesis by long-term cultured cell line established from human hepatoblastoma.

Consumption of plant sterol- or stanol-enriched margarines by statin users results in an additional LDL-cholesterol reduction of approximately 10 %, which may be larger than the average decrease of 3–7 % achieved by doubling the statin dose. However, whether this effect persists in the long term is not known. Therefore, we examined in patients already on stable statin treatment the effects of 85 weeks of plant sterol and stanol ester consumption on the serum lipoprotein profile, cholesterol metabolism, and bile acid synthesis. For this, a double-blind randomised trial was designed in which fifty-four patients consumed a control margarine with no added plant sterols or stanols for 5 weeks (run-in period). For the next 85 weeks, seventeen subjects continued with the control margarine and the other two groups with either a plant sterol (n18) or plant stanol (n19) (2·5 g/d each) ester-enriched margarine. Blood was sampled at the end of the run-in period and every 20 weeks during the intervention period. Compared with the control group, plant sterol and stanol ester consumption reduced LDL-cholesterol by 0·28 mmol/l (or 8·7 %;P = 0·08) and 0·42 mmol/l (13·1 %;P = 0·006) respectively after 85 weeks. No effects were found on plasma concentrations of oxysterols or 7α-hydroxy-4-cholesten-3-one, a bile acid synthesis marker. We conclude that long-term consumption of both plant sterol and stanol esters effectively lowered LDL-cholesterol concentrations in statin users.

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Pyrrolizidine Alkaloids Disturb Bile Acid Homeostasis in the Human Hepatoma Cell Line HepaRG

Foods ◽

10.3390/foods10010161 ◽

2021 ◽

Vol 10 (1) ◽

pp. 161

Author(s):

Julia Waizenegger ◽

Josephin Glück ◽

Marcus Henricsson ◽

Claudia Luckert ◽

Albert Braeuning ◽

...

Keyword(s):

Bile Acid ◽

Bile Acids ◽

Cell Line ◽

Pyrrolizidine Alkaloids ◽

Hepatoma Cell ◽

Acid Synthesis ◽

Bile Acid Synthesis ◽

Hepatoma Cell Line ◽

Human Hepatoma ◽

Human Hepatoma Cell

1,2-unsaturated pyrrolizidine alkaloids (PAs) belong to a group of secondary plant metabolites. Exposure to PA-contaminated feed and food may cause severe hepatotoxicity. A pathway possibly involved in PA toxicity is the disturbance of bile acid homeostasis. Therefore, in this study, the influence of four structurally different PAs on bile acid homeostasis was investigated after single (24 h) and repeated (14 days) exposure using the human hepatoma cell line HepaRG. PAs induce a downregulation of gene expression of various hepatobiliary transporters, enzymes involved in bile acid synthesis, and conjugation, as well as several transcription regulators in HepaRG cells. This repression may lead to a progressive impairment of bile acid homeostasis, having the potential to accumulate toxic bile acids. However, a significant intracellular and extracellular decrease in bile acids was determined, pointing to an overall inhibition of bile acid synthesis and transport. In summary, our data clearly show that PAs structure-dependently impair bile acid homeostasis and secretion by inhibiting the expression of relevant genes involved in bile acid homeostasis. Furthermore, important biliary efflux mechanisms seem to be disturbed due to PA exposure. These mole-cular mechanisms may play an important role in the development of severe liver damage in PA-intoxicated humans.

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Oral Cholic Acid for Hereditary Defects of Primary Bile Acid Synthesis: A Safe and Effective Long-term Therapy

Gastroenterology ◽

10.1053/j.gastro.2009.07.043 ◽

2009 ◽

Vol 137 (4) ◽

pp. 1310-1320.e3 ◽

Cited By ~ 61

Author(s):

Emmanuel Gonzales ◽

Marie F. Gerhardt ◽

Monique Fabre ◽

Kenneth D.R. Setchell ◽

Anne Davit–Spraul ◽

...

Keyword(s):

Bile Acid ◽

Cholic Acid ◽

Acid Synthesis ◽

Bile Acid Synthesis ◽

Term Therapy ◽

Long Term Therapy ◽

Primary Bile Acid

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Bile acid synthesis disorders in Japan: long-term outcome and chenodeoxycholic acid treatment

10.21203/rs.2.22018/v1 ◽

2020 ◽

Author(s):

Akihiko Kimura ◽

Tatsuki Mizuochi ◽

Hajime Takei ◽

Akira Ohtake ◽

Jun Mori ◽

...

Keyword(s):

Bile Acid ◽

Chenodeoxycholic Acid ◽

Low Dose ◽

Acid Synthesis ◽

Bile Acid Synthesis ◽

Term Outcome ◽

Long Term Outcome ◽

Reductase Deficiency ◽

Clinical Records

Abstract Background: We encountered 7 Japanese patients with bile acid synthesis disorders (BASD) over 21 years between 1996 and 2017. Diagnoses were made by bile acid and genetic analyses. We gave low-dose, long-term chenodeoxycholic acid (CDCA) treatment to 5 of the patients, who had 3β-hydroxy-Δ 5 -C 27 -steroid dehydrogenase/isomerase (3β-HSD) deficiency (n=3) or Δ 4 -3-oxosteroid 5β-reductase (5β-reductase) deficiency (n=2). Another patient with the latter diagnosis whose bile acid analyses had mitigating features was maintained on ursodeoxycholic acid according to parental preferences and now remains healthy after discontinuation of treatment. A patient with oxysterol 7α-hydroxylase deficiency developed liver failure and fully recovered after successful liver transplantation. We used clinical records to clarify long-term outcome and value of CDCA in the other patients. Efficacy of CDCA treatment was evaluated in the 5 patients given a low dose (5 to 10 mg/kg/day) for a long term. Results: Medians with ranges of current patient ages and duration of CDCA treatment are10 years (8 to 43) and 10 years (8 to 21), respectively. All 7 patients, who had homozygous or compound heterozygous mutations in the HSD3B7 , SRD5B1 , or CYP7B1 gene, are currently in good health without liver dysfunction. In the 5 patients with CDCA treatment, hepatic function gradually improved following initiation. No adverse effects were noted. Conclusions: We concluded that low-dose CDCA treatment is effective in 3β-HSD deficiency and 5β-reductase deficiency, as cholic acid has been in other countries. BASD carry a good prognosis following early diagnosis and initiation of long-term, low-dose CDCA treatment.

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Short-, medium- and long-term effects of ursodeoxycholic acid (UDCA) on cholesterol and bile acid synthesis in healthy humans

Gastroenterology ◽

10.1016/s0016-5085(00)81649-2 ◽

2000 ◽

Vol 118 (4) ◽

pp. A1439

Author(s):

S. Fischer ◽

K. Thiessen ◽

G.H. Sauter ◽

K. Parhofer ◽

D. Juengst

Keyword(s):

Bile Acid ◽

Ursodeoxycholic Acid ◽

Acid Synthesis ◽

Bile Acid Synthesis ◽

Long Term Effects ◽

Healthy Humans

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JNK-mediated disruption of bile acid homeostasis promotes intrahepatic cholangiocarcinoma

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2002672117 ◽

2020 ◽

Vol 117 (28) ◽

pp. 16492-16499

Author(s):

Elisa Manieri ◽

Cintia Folgueira ◽

María Elena Rodríguez ◽

Luis Leiva-Vega ◽

Laura Esteban-Lafuente ◽

...

Keyword(s):

Bile Acid ◽

Intrahepatic Cholangiocarcinoma ◽

Cholesterol Metabolism ◽

Metabolic Stress ◽

Signal Transduction Pathway ◽

Acid Synthesis ◽

Bile Acid Synthesis ◽

Gene Ablation ◽

Jnk Inhibitors

Metabolic stress causes activation of the cJun NH2-terminal kinase (JNK) signal transduction pathway. It is established that one consequence of JNK activation is the development of insulin resistance and hepatic steatosis through inhibition of the transcription factor PPARα. Indeed, JNK1/2 deficiency in hepatocytes protects against the development of steatosis, suggesting that JNK inhibition represents a possible treatment for this disease. However, the long-term consequences of JNK inhibition have not been evaluated. Here we demonstrate that hepatic JNK controls bile acid production. We found that hepatic JNK deficiency alters cholesterol metabolism and bile acid synthesis, conjugation, and transport, resulting in cholestasis, increased cholangiocyte proliferation, and intrahepatic cholangiocarcinoma. Gene ablation studies confirmed that PPARα mediated these effects of JNK in hepatocytes. This analysis highlights potential consequences of long-term use of JNK inhibitors for the treatment of metabolic syndrome.

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Short-medium- and long-term effect of ursodeoxycholic acid on cholesterol an bile acid synthesis in healthy humans

Gastroenterology ◽

10.1016/s0016-5085(08)81923-3 ◽

2001 ◽

Vol 120 (5) ◽

pp. A387

Author(s):

Kai Thiessen ◽

Gerd Sauter ◽

Klaus Georg Parhofer ◽

Dieter Juengst ◽

Sven Fischer

Keyword(s):

Bile Acid ◽

Ursodeoxycholic Acid ◽

Acid Synthesis ◽

Bile Acid Synthesis ◽

Term Effect ◽

Healthy Humans ◽

Long Term Effect

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FGF21 acts as a negative regulator of bile acid synthesis

Journal of Endocrinology ◽

10.1530/joe-17-0727 ◽

2018 ◽

Vol 237 (2) ◽

pp. 139-152 ◽

Cited By ~ 13

Author(s):

Michelle M Chen ◽

Clarence Hale ◽

Shanaka Stanislaus ◽

Jing Xu ◽

Murielle M Véniant

Keyword(s):

Bile Acid ◽

Acid Metabolism ◽

Acid Synthesis ◽

Bile Acid Synthesis ◽

Negative Regulator ◽

Bile Acid Metabolism ◽

Primary Hepatocytes ◽

Term Administration ◽

Long Acting

Fibroblast growth factor 21 (FGF21) is a potent regulator of glucose and lipid homeostasis in vivo; its most closely related subfamily member, FGF19, is known to be a critical negative regulator of bile acid synthesis. To delineate whether FGF21 also plays a functional role in bile acid metabolism, we evaluated the effects of short- and long-term exposure to native FGF21 and long-acting FGF21 analogs on hepatic signal transduction, gene expression and enterohepatic bile acid levels in primary hepatocytes and in rodent and monkey models. FGF21 acutely induced ERK phosphorylation and inhibited Cyp7A1 mRNA expression in primary hepatocytes and in different rodent models, although less potently than recombinant human FGF19. Long-term administration of FGF21 in mice fed a standard chow diet resulted in a 50–60% decrease in bile acid levels in the liver and small intestines and consequently a 60% reduction of bile acid pool size. In parallel, colonic and fecal bile acid was decreased, whereas fecal cholesterol and fatty acid excretions were elevated. The long-acting FGF21 analog showed superiority to recombinant human FGF21 and FGF19 in decreasing bile acid levels with long duration of effect action in mice. Long-term administration of the long-acting FGF21 analogs in obese cynomolgus monkeys suppressed plasma total bile acid and 7α-hydroxy-4-cholesten-3-one levels, a biomarker for bile acid synthesis. Collectively, these data reveal a previously unidentified role of FGF21 in bile acid metabolism as a negative regulator of bile acid synthesis.

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