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Tauroursodeoxycholic Acid

TUDCA is a water soluble bile acid. It shows great potency in treating cholestasis (bile acid backup in the liver) as the water soluble bile acids counteract the toxicity of regular bile acids. Can also protect and rehabilitate the liver, and general protects cells; very promising molecule.

Our evidence-based analysis on tauroursodeoxycholic acid features 77 unique references to scientific papers.

Research analysis led by and reviewed by the Examine team.
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Research Breakdown on Tauroursodeoxycholic Acid

1Sources and Structure


Tauroursodeoxycholic Acid (Tauro- Urso- Deoxy- Cholic), commonly referred to as TUDCA, is a derivative of a secondary bile salt secreted from the liver. When bile salts created by the liver reach the intestines, they can be converted into UDCA (ursodeoxycholic acid) by intestinal bacteria[1] and TUDCA is created when a taurine molecule is added to the structure.[2] Both of these related molecules are known as hydrophilic bile acids.[2]

It is a common constituent of bile acids, and is in high amounts in the bile acids of bears where is has traditionally been extracted.



2.1Absorption and bioavailability

After oral administration, TUDCA appears to be more effective in raising bile concentrations of UDCA (and downstream effects, such as reducing liver enzyme levels) than UDCA itself; this is most likely due to the taurine group enhancing bioavailability.[3] [4] The process of conjugating UDCA with taurine is a rate-limiting step, and this rate-limit is avoided with supplementation of TUDCA.[5]


Orally administered TUDCA, at 750mg daily, was able to significantly change the UDCA content of serum, fecal, and urinary bile measurements after 2 months of supplementation; suggesting systemic distribution.[3] Only a small amount of UDCA in serum is unconjugated, as most is bound to taurine or glycine; oral administration of 1500mg for 6 months has an unconjugated UDCA contant of 0.6+/-0.3% in serum.[4]

Orally administered TUDCA is able to reach neuronal tissue in rats.[6]

3Interactions with the Endoplasmic Reticulum

The endoplasmic reticulum (ER) is an organelle in cells that extends from the nucleus and forms an interconnected network of pathways in the cell. The ER has a role in folding protein structures, and oxidative stress can cause the ER to misfold or unfold proteins in a response called the 'Unfolding Protein Response' (UPR); which is an adaptive self-protective response in cells, either reversing the stressor or (if it fails to do so) signalling cell death.[7] TUDCA is seen as an ER stress response attenuator, and is able to block cell death induced by the adaptive UPR and preserve cell function.[2][8][9]

3.1ER stress and Ischemia/Reperfusion

Via reducing the unfolding protein response, TUDCA has been shown to reduce damage to organs from acute oxygen deprivation such as acute kidney trauma,[10] surgery on the liver,[9][11][12] and stroke.[13] It has also been shown to inhibit neovascularization in diabetic rats, which is induced by similar mechanisms above.[14]

4Interactions with the Liver

Endoplasmic Reticulum (ER) stress appears to be a significant regulator in liver cells (hepatocytes) of inflammation and injury[12] and in part insulin signalling.[15] Tauroursodeoxycholic Acid (TUDCA), as a suppressor of protein unfolding and ER stress, may confer a therapeutic and rehabilitative role.

4.1Cell death and count

TUDCA has been shown to improve liver healing rates in both steatotic and non-steatotic livers via ER stress reduction after ischemia/reperfusion.[9] TUDCA, in this study, resulted in less cell death via alleviating a mechanism known to accelerate cell apoptosis and also suppressed the actions of IRE-1 and PKR-like ER kinase, two pathways known to induce protein unfolding.[9] This cell protective effect has also been seen in liver cells undergoing cold storage[16] as well as the epithelial cells of bile ducts, which are damaged during chronic hepatitis.[17] These latter benefits are mediated via PKCa and intracellular Ca2+[17] and may be dependent on basic levels of dietary methionine and choline.[18]

After administration in men with chronic liver disease, 10-13mg TUDCA daily for 3 months appears to enhance the rate of hepatocyte proliferation as well.[19]

Beyond TUDCA's primary treatment purpose (Cholestasis, next section) TUDCA also appears to have beneficial modulation of cells in the liver, promoting regeneration and reducing cell death. May not be relevant in an already health liver (due to high regeneration rates already), but nice for unhealthy livers


Cholestasis is a condition in which bile flow from the liver is distrupted in some manner. UDCA and TUDCA are currently one of the first lines of treatment for a variety of cholestatic syndromes.[2]

Accumulation of bile acids in the liver during periods of impeded intestinal secretion (cholestasis) can cause cell death in hepatocytes secondary to the bile acid's detergent-like effects,[20][21][22] and UDCA/TUDCA confer protective effects in this scenario. The detergent-like effects are related to bile acid's hydrophobicity and lipid solubilizing actions, yet UDCA/TUDCA are highly hydrophilic and unlikely to possess the same toxicity.[23][24] 

The mechanism of protection may be through competitive antagonism of harmful bile salts actions on hepatocytes.[25] This, in conjunction with TUDCA supplementation increasing the relative amount of hydrophilic bile salts (UDCA, TUDCA) relative to the harmful salts exerts an overall protective effect. The increase in UDCA seen with supplementation is a diminishing response dose-dependent relationship with 500mg, 1000mg, and 1500mg increasing the bile content of TUDCA from 2.9% (in persons with Primary Biliary Cirrhosis) to 34.4+/-4.5%, 32.8+/-2.8%, and 41.6+/-3%, respectively.[4] The most effective dose for this beneficial partitioning of bile salts, based on plotted curves from serum and bile analysis, may be 15-20mg/kg bodyweight TUDCA.[4]

For short term treatment of bile acid complications and cholestasis, TUDCA appears to be very potent and reliable. Used in clinical settings for treatment of cholestasis as well.


Gallstones (made of cholesterol) may be treated in a litholytic manner with bile acids,[26] dissolving them to a size in which they may be passed. The process of dissolving gallstones made of cholesterol is sometimes also referred to as cholelitholytic[27] (with litholytic being a more general term, and used with more frequency for kidney stones). Cholesterol gallstones are approximately 75% of all hepatic gallstones (at least in Western countries[28][29]) and are thought to be the only formation of gallstone able to be dissolved with bile acids.[30]

Gallstones may become opaque, which is thought to indicate their inability to dissolve (and thus, a failure of litholysis treatment);[31] the opacity appears to be related to calcium deposition in the cholesterol gallstone, and appears to make gallstones resistant to bile acid induced cholelitholysis.[32][30] The opaque gallstones are either black (around 20% in total and consisting of calcium phosphate and/or carbonate with insoluble bilirubin pigment and cholesterol) or brown (around 5% overall containing calcium bilirubinate, calcium palmitate, stearate and cholesterol).[33][30]

Gallstones can form in the liver from cholesterol, and administration of bile acids is thought to dissolve the gallstones to a level where they may be passed; this dissolution appears to not influence all gallstones, with gallstones having a calcium content being resistant to bile acids.

Therapy tends to consist of a nightly dose of bile acids (UDCA or TUDCA) paired with a low cholesterol diet to encourage cholesterol efflux.[34][35] It should be noted that therapy with oral bile acids is not first-line, and that usually a minimal amount of persons with gallstones respond to UDCA or TUDCA (10% or less[36]); standard practise suggests that it be limited to persons unfit for surgery with small (5mm or less diameter) uncalcified and cholesterol rich gallstones.[30]

In looking at the rate of failure (formation of opacity during treatment of bile acids), there do not appear to be any significant differences between TUDCA, UDCA, or another bile acid known as CDCA.[37]

Treatment of gallstones with TUDCA is used in clinical settings, but is not the first-line treatment and requires certain conditions to be met (small uncalcified gallstone of mostly cholesterol) to be effective. When comparing TUDCA against other bile acids, there do not appear to be significant differences in efficacy

5Interactions with Neurology

5.1Huntington's Disease

Oral administration of TUDCA in rats was shown to be protective against a toxin which induces Huntington's Disease,[6][38] and was later shown in rats to be neuroprotective in a model of Huntington's Disease without said toxin; reducing neuronal death and improving symptoms.[39]

These protective effects may also extend to dopaminergic neurons and Parkinson's Disease,[40][41] but no practical oral ingestion studies exist.


In vitro studies suggest that TUDCA incubation alongside beta-amyloid pigment, an insoluble protein involved in the pathology of Alzheimer's, was able to prevent beta-amyloid induced cell death in rat neuronal and astrocyte cells,[42] neuroblastoma cells,[43] primary corticol neurons,[44] and PC12 cells.[45] Mitochondrial permeability associated with beta-amyloid induced toxicity is decreased with TUDCA[42] and inhibits adverse changes in the mitochondria as a result of beta-amyloid toxicity.[46]

However, TUDCA has not been implicated in actually reducing beta-amyloid levels. This suggests protective effects on cells independent of beta-amyloid presence.[2]


TUDCA has shown neuroprotective actions against stroke and acute neurological injury[47][13]

In general, TUDCA appears to be quite protective of cells and this applies to the brain as well. Orally ingested TUDCA is able to reach neuronal tissue, but relevance to humans with TUDCA ingestion has not yet been shown

6Interactions with Glucose metabolism


TUDCA has been demonstrated to restore glucose homeostasis in a cell culture as well as diabetic mice and increase insulin sensitivity in liver, muscle, and adipose tissue.[8] ER stress has been linked to both obesity as well as diabetes,[48] possibly through increased ER stress inducing an adaptive unfolded protein response, and inhibiting insulin signalling via activating the JNK pathway via IRE-1.[49][50] Whether ER stress, per se, is a causative step in muscle tissue is not known and may be doubtful.[51]

A study in mice at 0.5mg/kg bodyweight TUDCA suggest that thyroid hormone deiodinase enyzmes, specifically D2, play a role. Supplementation of this dose in rats has been shown to normalize glucose tolerance[8] but this effect is not seen in mice without the D2 enzyme or mRNA (Dio2−/− mice).[52]

6.2Interactions with Beta-cells

An in vitro study on the interactions of TUDCA and beta-cells found that TUDCA failed to normalize insulin resistance when glucose was incubated with a cell at 6.5mmol/L but restored function at higher levels of glycermia (13 and 22mmol/L) without affecting insulin content of the cells.[53] Hyperglycemia was able to reduce mRNA production of preproinsulin (insulin precursor), and this reduction was prevented with TUDCA.[53] 13mmol/L correlates to the cellular concentration of hyperglycemia[54] and is physiologically relevant. These effects seem to be secondary to reducing ER stress.[53]


TUDCA, at 1,750mg daily in obese persons without NAFLD nor type II diabetes over 4 weeks, was able to reduce insulin resistance in skeletal muscle as assessed by increased phosphorylation of Akt and IRS-1 in response to a standardized test meal.[55] No influence on insulin induced JNK activation was seen in myocytes.

Preliminary, but TUDCA appears to be able to protect cells from dysfunction associated with hyperglycemia and may reduce the effects of insulin resistance before they happen (beta-cells) and even therapeutically with the potency of some diabetic pharmaceuticals (in regards to the liver and skeletal muscle)

7Interactions with Fat Mass and Obesity

7.1Thyroid and Metabolic Rate

Circulating Bile Acids (those not found in the liver, but the blood) have been found to be correlated with energy expenditure in humans. With correlation coefficients of 0.648 in healthy persons and 0.833 in those with cirrhosis,[56] although other smaller studies (n=24) find no such correlations.[57]

TUDCA has been shown in vitro to increase protein content and mRNA levels for the deiodinase enzyme D2 in cells expressing this protein normally; this protein converts relatively low-activity thyroid hormone T4 to T3, and incubation with TUDCA was able to double protein content of the enzyme and increase T3 levels at concentrations between 100-800uM, reaching three-fold increases at the highest level.[52] Although the delayed response to max potency and prior evidence that deiodinases are regulated post-transcriptionally,[58] the authors noted that the increase in deiodinase mRNA (Dio2) makes it unlikely that the effects seen are secondary to protein stabilization.[52]

When fed to mice at 0.5mg/kg bodyweight, TUDAC was unable to induce fat loss over 7 days but induced a change in respiratory quotient by 5% towards using fatty acids as substrate.[52] Serum levels of T3 and T4 were unchanged in these animals, suggesting localized usage of T3 or a mechanism independent of thyroid hormones.[52] Another report noted small but statistically significant decreases in body weight in mice over 15-30 days, but did not specify dose of TUDCA used.[8] It is possible that these effects are through increasing activity of the D2 receptor, which has been demonstrated in animals with 0.5% cholic acid in the diet that induced similar effects such as an increase in metabolic rate alongside a decrease in respiratory quotient (indicative of a greater % of energy from fatty acids).[59]

These mechanisms may be relevant to humans due to muscle cells expressing the same D2 receptor, and at least cholic acid has been found to increase human myocyte mRNA of this receptor (TGR5) and similar trends were found with all tested bile acids.[59]


It has been noted that the obesity-related suppression of adiponectin content may be related to ER stress, and one rat study has shown TUDCA in diet-induced obesity was able to increase circulating adiponectin levels via the protein DsbA-L.[60]


After ingestion of 1,750mg TUDCA for 4 weeks in obese but otherwise healthy persons, no significant effects were observed on body fat or weight.[55] Insulin sensitivity was improved in skeletal muscle and the liver, but not in the adipose (body fat) tissue of these persons.[55] This differs from previous rat studies[8] and may be due to the dose in the rat studies being higher.

Appears to have mechanisms to augment Thryoid Hormone actions and induce fat loss, but the dose may be too high to be practically relevant

8Interactions with Cancer Biology

8.1Cell proliferation

In a lot of ways cancer cells are analogous to weeds in an otherwise well-groomed lawn. The weeds tend to grow bigger, spread faster, and can displace the slower growing, more regulated grass to the detriment of the lawn. Likewise, cancer cells are dangerous because they have mutated away from the normal/ healthy cell phenotype, allowing them to avoid all of the molecular checks and balances that keep normal cells healthy and well-behaved. In the absence of well-controlled cell cycle regulation, cancer cells tend to proliferate at a pathological rate, compromising the function of healthy cells, tissues and organs and eventually leading to organ failure and death.

Cancer cells are often associated with uncontrolled proliferation which can displace normal, healthy cells and compromise organ function.

A study on the colon cancer cell lines HT29 and HCT116 revealed that UDCA can suppress cell proliferation in vitro, which was associated with inhibition of both the G1/S and G2/M transition phases of the cell cycle.[61] The anti-proliferative mechanism occurred in-part through UDCA-induced expression of the cell cycle inhibitor proteins p27 and p21. UDCA also suppressed levels of the cyclin-dependent kinase (CDK) proteins CDK2, CDK4, and CDK6. Since CDKs play an important role in cell cycle progression, these results revealed that UDCA inhibits cell cycle progression through multiple mechanisms.

UDCA treatment was also associated with reduced intracellular ROS levels.[61] In turn, diminished ROS levels contributed to increased Erk1/2 activation which was previously shown to induce cell cycle arrest in colonic epithelial cells.[62] [63] [64] Thus, UDCA inhibits the tendency of colonic cancer cells to rapidly progress through the cell cycle, raising the possibility that it may be useful adjunct to chemotherapy in certain cancers. More research is neeeded to determine whether the anti-proliferative properties of UDCA or TUDCA are also observed in animals or humans.

UDCA suppresses cell proliferation in colon cancer cells through multiple mechanisms.

9Nutrient-Nutrient Interactions


Alcohol, or drinking ethanol, can be as fun as it is damaging to the liver.

TUDCA, and its taurine-free conjugate UDCA, have been shown to attenuate the reduction of bioenergetics in a liver cell after incubation with acetaldehyde (metabolite of alcohol that does the damage) as well as significantly reduce cell death induced by ethanol when TUDCA is at 0.1mM concentration and UDCA at 0.01mM.[65] Concentrations of 0.5mM of both have shown similar mechanistic protection but slightly weaker,[66] but dose-response is not present as higher concentrations (>0.1mM) were reported to induce cell death.[65] TUDCA appeared to be geared towards preserving membrane function while UDCA was more potent at preserving mitochondrial function.[65]

Most critically, these benefits were seen with co-incubation or adminstration of them both at the same time.[66][65] When pre-loaded before ethanolic insult, they have been shown to exacerbate damage to liver cells.[65] These effects may be secondary to alterations in the lipid membrane of cells with TUDCA/UDCA exposure.[67]

Might alleviate alcohol's adverse effects on the liver, but appears to be needed to be taken after drinking and may be damaging if taken before

10Safety and Toxicity

10.1Human Data

Usage of 500mg TUDCA daily for one year (in persons after liver transplants) was not assocaited with any adverse effects[68] and in otherwise healthy obese persons doses of 1,750mg have been well tolerated for up to 4 weeks.[55]

In persons with primary biliary cirrhosis, 750mg daily for 2 months was not associated with any adverse effects[3] and a similar population was able to tolerate 1,500mg daily for 6 months with no adverse effects.[4]

Although TUDCA/UDCA have shown beneficial effects in a number of different experimental and clinical models as noted thus far, a randomized controlled trial evaluating the efficacy of UDCA treatment in patients with primary sclerosing cholangitis (PSC) suggests that high doses for long periods of time may be toxic.[69]

PSC is a rare, chronic liver disease characterized by inflammatory fibrosis of the bile ducts and is typically associated with biliary cirrhosis and portal hypertension, which eventually progress to liver failure.[70] In some cases cholangiocarcinoma, (bile duct cancer) can also develop.

UDCA has been tested as a possible treatment for primary sclerosing cholangitis (PSC), a rare liver disease.

Given the poor prognosis of PSC, there have been a number of trials testing the efficacy of UDCA for treating this disease. A few pilot trials testing UDCA in a dose range of 10-15 mg/kg bodyweight/day did show improvements in liver enzymes (an indicator of liver stress), and in certain cases liver histology (i.e. the appearance of liver biopsy sections under a microscope), although patient symptoms were not improved.[71][72][73] 

Given the promising improvements of clinical markers but lack of effect on symptoms in these pilot studies, researchers reasoned that the dose and/or duration of UDCA treatment was insufficient to alleviate symptoms. This was addressed in the Lindor trial, where patients with PSC were administered 28-30 mg/kg bodyweight/day UDCA or a placebo.[69] Treatments were assigned in a randomized, double-blinded fashion and liver biopsies were taken before the trial and after 5 years. The investigators were specifically examining the ability of UDCA to reduce or delay the following primary outcomes: development of cirrhosis, bile duct cancer, liver transplantation, or death. Ultimately the study was terminated after 6 years, because patients receiving the UDCA treatment were substantially worse-off than those who took the placebo. Although liver enzyme levels decreased more in the UDCA group, 39% of these patients reached one of the primary outcomes by the end of the study. In contrast, only 19% of patients that received the placebo reached a primary endpoint. Overall, patients receiving UDCA were 2.3x more likely to reach a primary endpoint and 2.1x more likely to die or require liver transplantation.[69]

Patients in the Lindor trial were 2.3x more likely to reach an adverse primary endpoint and 2.1x more likely to die or require a liver transplant after several years of high-dose UDCA treatment.

Why was high-dose UDCA so toxic in PSC patients?

Although unexpected, the authors of the Lindor study speculated that high-dose UDCA may cause hepatocyte necrosis caused in part by the increased amount of bile duct obstruction associated with advanced PSC. Alternatively, high levels of UDCA in the right colon could lead to increased levels of toxic bile acids.[74]

<High-dose, long term UDCA treatment may be contraindicated in patients with advanced primary sclerosing cholangitis (PSC). More research is needed to determine the mechanism of toxicity, and in which patient populations usage may be toxic.


Infusion studies find that rates of TUDCA infusion from 4-32umol/kg/min are not associated with any abnormal liver histological findings.[25]


  1. ^ Lepercq P, et al. Increasing ursodeoxycholic acid in the enterohepatic circulation of pigs through the administration of living bacteria. Br J Nutr. (2005)
  2. ^ a b c d e Amaral JD, et al. Bile acids: regulation of apoptosis by ursodeoxycholic acid. J Lipid Res. (2009)
  3. ^ a b c Invernizzi P, et al. Differences in the metabolism and disposition of ursodeoxycholic acid and of its taurine-conjugated species in patients with primary biliary cirrhosis. Hepatology. (1999)
  4. ^ a b c d e Setchell KD, et al. Metabolism of orally administered tauroursodeoxycholic acid in patients with primary biliary cirrhosis. Gut. (1996)
  5. ^ Zouboulis-Vafiadis I, Dumont M, Erlinger S. Conjugation is rate limiting in hepatic transport of ursodeoxycholate in the rat. Am J Physiol. (1982)
  6. ^ a b Keene CD, et al. A bile acid protects against motor and cognitive deficits and reduces striatal degeneration in the 3-nitropropionic acid model of Huntington's disease. Exp Neurol. (2001)
  7. ^ Bernales S, Papa FR, Walter P. Intracellular signaling by the unfolded protein response. Annu Rev Cell Dev Biol. (2006)
  8. ^ a b c d e Ozcan U, et al. Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes. Science. (2006)
  9. ^ a b c d Ben Mosbah I, et al. Endoplasmic reticulum stress inhibition protects steatotic and non-steatotic livers in partial hepatectomy under ischemia-reperfusion. Cell Death Dis. (2010)
  10. ^ Gao X, et al. The nephroprotective effect of tauroursodeoxycholic Acid on ischaemia/reperfusion-induced acute kidney injury by inhibiting endoplasmic reticulum stress. Basic Clin Pharmacol Toxicol. (2012)
  11. ^ Hertl M, et al. In vivo protection of the pig liver against ischemia/reperfusion injury by tauroursodeoxycholate. Langenbecks Arch Surg. (1999)
  12. ^ a b Anderson CD, et al. Endoplasmic reticulum stress is a mediator of posttransplant injury in severely steatotic liver allografts. Liver Transpl. (2011)
  13. ^ a b Rodrigues CM, et al. Neuroprotection by a bile acid in an acute stroke model in the rat. J Cereb Blood Flow Metab. (2002)
  14. ^ Amin A, et al. Chronic inhibition of endoplasmic reticulum stress and inflammation prevents ischaemia-induced vascular pathology in type II diabetic mice. J Pathol. (2012)
  15. ^ Achard CS, Laybutt DR. Lipid-induced endoplasmic reticulum stress in liver cells results in two distinct outcomes: adaptation with enhanced insulin signaling or insulin resistance. Endocrinology. (2012)
  16. ^ Falasca L, et al. Protective role of tauroursodeoxycholate during harvesting and cold storage of human liver: a pilot study in transplant recipients. Transplantation. (2001)
  17. ^ a b Marzioni M, et al. Ca2+-dependent cytoprotective effects of ursodeoxycholic and tauroursodeoxycholic acid on the biliary epithelium in a rat model of cholestasis and loss of bile ducts. Am J Pathol. (2006)
  18. ^ Henkel AS, et al. Reducing endoplasmic reticulum stress does not improve steatohepatitis in mice fed a methionine- and choline-deficient diet. Am J Physiol Gastrointest Liver Physiol. (2012)
  19. ^ Panella C, et al. Does tauroursodeoxycholic acid (TUDCA) treatment increase hepatocyte proliferation in patients with chronic liver disease. Ital J Gastroenterol. (1995)
  20. ^ Solá S, et al. Membrane structural changes support the involvement of mitochondria in the bile salt-induced apoptosis of rat hepatocytes. Clin Sci (Lond). (2002)
  21. ^ Schölmerich J, et al. Influence of hydroxylation and conjugation of bile salts on their membrane-damaging properties--studies on isolated hepatocytes and lipid membrane vesicles. Hepatology. (1984)
  22. ^ Oelberg DG, Lester R. Cellular mechanisms of cholestasis. Annu Rev Med. (1986)
  23. ^ Attili AF, et al. Bile acid-induced liver toxicity: relation to the hydrophobic-hydrophilic balance of bile acids. Med Hypotheses. (1986)
  24. ^ Yousef IM, et al. Liver cell membrane solubilization may control maximum secretory rate of cholic acid in the rat. Am J Physiol. (1987)
  25. ^ a b Piazza F, et al. Competition in liver transport between chenodeoxycholic acid and ursodeoxycholic acid as a mechanism for ursodeoxycholic acid and its amidates' protection of liver damage induced by chenodeoxycholic acid. Dig Liver Dis. (2000)
  26. ^ Salen G, Tint GS, Shefer S. Treatment of cholesterol gallstones with litholytic bile acids. Gastroenterol Clin North Am. (1991)
  27. ^ Cetta F, Montalto G, Pacchiarotti MC. Gallstone opacification during cholelitholytic treatment. Am J Gastroenterol. (1997)
  28. ^ Diehl AK. Epidemiology and natural history of gallstone disease. Gastroenterol Clin North Am. (1991)
  29. ^ Attili AF, et al. Factors associated with gallstone disease in the MICOL experience. Multicenter Italian Study on Epidemiology of Cholelithiasis. Hepatology. (1997)
  30. ^ a b c d Therapy of gallstone disease: What it was, what it is, what it will be.
  31. ^ Lanzini A, Northfield TC. Pharmacological treatment of gallstones. Practical guidelines. Drugs. (1994)
  32. ^ Portincasa P, et al. Medicinal treatments of cholesterol gallstones: old, current and new perspectives. Curr Med Chem. (2009)
  33. ^ Diseases of the Liver and Biliary System, Eleventh Edition.
  34. ^ Lanzini A, Facchinetti D, Northfield TC. Maintenance of hepatic bile acid secretion rate during overnight fasting by bedtime bile acid administration. Gastroenterology. (1988)
  35. ^ Kupfer RM, Maudgal DP, Northfield TC. Gallstone dissolution rate during chenic acid therapy. Effect of bedtime administration plus low cholesterol diet. Dig Dis Sci. (1982)
  36. ^ Paumgartner G, Pauletzki J, Sackmann M. Ursodeoxycholic acid treatment of cholesterol gallstone disease. Scand J Gastroenterol Suppl. (1994)
  37. ^ Bazzoli F, et al. Acquired gallstone opacification during cholelitholytic treatment with chenodeoxyholic, ursodeoxycholic, and tauroursodeoxycholic acids. Am J Gastroenterol. (1995)
  38. ^ Rodrigues CM, et al. Tauroursodeoxycholic acid partially prevents apoptosis induced by 3-nitropropionic acid: evidence for a mitochondrial pathway independent of the permeability transition. J Neurochem. (2000)
  39. ^ Keene CD, et al. Tauroursodeoxycholic acid, a bile acid, is neuroprotective in a transgenic animal model of Huntington's disease. Proc Natl Acad Sci U S A. (2002)
  40. ^ Ved R, et al. Similar patterns of mitochondrial vulnerability and rescue induced by genetic modification of alpha-synuclein, parkin, and DJ-1 in Caenorhabditis elegans. J Biol Chem. (2005)
  41. ^ Duan WM, et al. Tauroursodeoxycholic acid improves the survival and function of nigral transplants in a rat model of Parkinson's disease. Cell Transplant. (2002)
  42. ^ a b Rodrigues CM, et al. Bilirubin and amyloid-beta peptide induce cytochrome c release through mitochondrial membrane permeabilization. Mol Med. (2000)
  43. ^ Ramalho RM, et al. Tauroursodeoxycholic acid modulates p53-mediated apoptosis in Alzheimer's disease mutant neuroblastoma cells. J Neurochem. (2006)
  44. ^ Ramalho RM, et al. Apoptosis in transgenic mice expressing the P301L mutated form of human tau. Mol Med. (2008)
  45. ^ Ramalho RM, et al. Inhibition of the E2F-1/p53/Bax pathway by tauroursodeoxycholic acid in amyloid beta-peptide-induced apoptosis of PC12 cells. J Neurochem. (2004)
  46. ^ Rodrigues CM, et al. Amyloid beta-peptide disrupts mitochondrial membrane lipid and protein structure: protective role of tauroursodeoxycholate. Biochem Biophys Res Commun. (2001)
  47. ^ Rodrigues CM, et al. Tauroursodeoxycholic acid reduces apoptosis and protects against neurological injury after acute hemorrhagic stroke in rats. Proc Natl Acad Sci U S A. (2003)
  48. ^ Ozcan U, et al. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science. (2004)
  49. ^ Hirosumi J, et al. A central role for JNK in obesity and insulin resistance. Nature. (2002)
  50. ^ Urano F, et al. Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1. Science. (2000)
  51. ^ Rieusset J, et al. Reduction of endoplasmic reticulum stress using chemical chaperones or Grp78 overexpression does not protect muscle cells from palmitate-induced insulin resistance. Biochem Biophys Res Commun. (2012)
  52. ^ a b c d e da-Silva WS, et al. The chemical chaperones tauroursodeoxycholic and 4-phenylbutyric acid accelerate thyroid hormone activation and energy expenditure. FEBS Lett. (2011)
  53. ^ a b c Tang C, et al. Glucose-induced beta cell dysfunction in vivo in rats: link between oxidative stress and endoplasmic reticulum stress. Diabetologia. (2012)
  54. ^ Boden G, et al. Effects of prolonged glucose infusion on insulin secretion, clearance, and action in normal subjects. Am J Physiol. (1996)
  55. ^ a b c d Kars M, et al. Tauroursodeoxycholic Acid may improve liver and muscle but not adipose tissue insulin sensitivity in obese men and women. Diabetes. (2010)
  56. ^ Ockenga J, et al. Plasma bile acids are associated with energy expenditure and thyroid function in humans. J Clin Endocrinol Metab. (2012)
  57. ^ Brufau G, et al. Plasma bile acids are not associated with energy metabolism in humans. Nutr Metab (Lond). (2010)
  58. ^ Sagar GD, et al. Ubiquitination-induced conformational change within the deiodinase dimer is a switch regulating enzyme activity. Mol Cell Biol. (2007)
  59. ^ a b Watanabe M, et al. Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. Nature. (2006)
  60. ^ Zhou L, et al. DsbA-L alleviates endoplasmic reticulum stress-induced adiponectin downregulation. Diabetes. (2010)
  61. ^ a b Kim EK, et al. Ursodeoxycholic acid inhibits the proliferation of colon cancer cells by regulating oxidative stress and cancer stem-like cell growth. PLoS One. (2017)
  62. ^ Meloche S, Pouysségur J. The ERK1/2 mitogen-activated protein kinase pathway as a master regulator of the G1- to S-phase transition. Oncogene. (2007)
  63. ^ Krishna-Subramanian S, et al. UDCA slows down intestinal cell proliferation by inducing high and sustained ERK phosphorylation. Int J Cancer. (2012)
  64. ^ Goulet AC, et al. Selenomethionine induces sustained ERK phosphorylation leading to cell-cycle arrest in human colon cancer cells. Carcinogenesis. (2005)
  65. ^ a b c d e Henzel K, et al. Toxicity of ethanol and acetaldehyde in hepatocytes treated with ursodeoxycholic or tauroursodeoxycholic acid. Biochim Biophys Acta. (2004)
  66. ^ a b Neuman MG, et al. Effect of tauroursodeoxycholic and ursodeoxycholic acid on ethanol-induced cell injuries in the human Hep G2 cell line. Gastroenterology. (1995)
  67. ^ Leuschner U, et al. TUDCA and UDCA are incorporated into hepatocyte membranes: different sites, but similar effects. Ital J Gastroenterol. (1995)
  68. ^ Angelico M, et al. One-year pilot study on tauroursodeoxycholic acid as an adjuvant treatment after liver transplantation. Ital J Gastroenterol Hepatol. (1999)
  69. ^ a b c Lindor KD, et al. High-dose ursodeoxycholic acid for the treatment of primary sclerosing cholangitis. Hepatology. (2009)
  70. ^ Maggs JR, Chapman RW. An update on primary sclerosing cholangitis. Curr Opin Gastroenterol. (2008)
  71. ^ O'Brien CB, et al. Ursodeoxycholic acid for the treatment of primary sclerosing cholangitis: a 30-month pilot study. Hepatology. (1991)
  72. ^ Beuers U, et al. Ursodeoxycholic acid for treatment of primary sclerosing cholangitis: a placebo-controlled trial. Hepatology. (1992)
  73. ^ Stiehl A, et al. Effect of ursodeoxycholic acid on liver and bile duct disease in primary sclerosing cholangitis. A 3-year pilot study with a placebo-controlled study period. J Hepatol. (1994)
  74. ^ Chapman RW. High-dose ursodeoxycholic acid in the treatment of primary sclerosing cholangitis: throwing the urso out with the bathwater?. Hepatology. (2009)
  75. Larghi A, et al. Ursodeoxycholic and tauro-ursodeoxycholic acids for the treatment of primary biliary cirrhosis: a pilot crossover study. Aliment Pharmacol Ther. (1997)
  76. Crosignani A, et al. Tauroursodeoxycholic acid for treatment of primary biliary cirrhosis. A dose-response study. Dig Dis Sci. (1996)
  77. Crosignani A, et al. Tauroursodeoxycholic acid for the treatment of HCV-related chronic hepatitis: a multicenter placebo-controlled study. Hepatogastroenterology. (1998)