Chenodeoxycholic Acid and Ursodeoxycholic Acid Effects in Endogenous Hypertriglyceridemias. A Controlled Double‐Blind Trial

Carulli, Nicola; Leòn, Maurizio Ponz de; Podda, Mauro; Zuin, Massimo; Strata, A; G, Frigerio; Digrisolo, Antonia

doi:10.1002/j.1552-4604.1981.tb01746.x

Cited by 51 publications

(26 citation statements)

References 15 publications

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“…We here investigated the effects of bile acids on TG homeostasis and confirmed that bile acids have a beneficial effect in hypertriglyceridemia (12,15,16,37). For these studies, we used KK-A y mice, a model for obesity and type 2 diabetes mellitus.…”

Section: Discussionmentioning

confidence: 69%

“…In humans, bile acid-binding resins induce the production of VLDL TGs (12)(13)(14), whereas treatment of cholesterol gallstones with the bile acid chenodeoxycholic acid (CDCA) has been shown to reduce hypertriglyceridemia (12,15,16). The mechanism underlying this reciprocal relationship between bile acid biosynthesis and TG production has remained elusive, but two possible explanations have been postulated.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Bile acids lower triglyceride levels via a pathway involving FXR, SHP, and SREBP-1c

Watanabe¹,

Wang²,

Moschetta³

et al. 2004

J. Clin. Invest.

290

324

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We explored the effects of bile acids on triglyceride (TG) homeostasis using a combination of molecular, cellular, and animal models. Cholic acid (CA) prevents hepatic TG accumulation, VLDL secretion, and elevated serum TG in mouse models of hypertriglyceridemia. At the molecular level, CA decreases hepatic expression of SREBP-1c and its lipogenic target genes. Through the use of mouse mutants for the short heterodimer partner (SHP) and liver X receptor (LXR) α and β, we demonstrate the critical dependence of the reduction of SREBP-1c expression by either natural or synthetic farnesoid X receptor (FXR) agonists on both SHP and LXRα and LXRβ. These results suggest that strategies aimed at increasing FXR activity and the repressive effects of SHP should be explored to correct hypertriglyceridemia. 1408The Nonstandard abbreviations used: acetyl-CoA carboxylase (ACC); acetyl-CoA synthetase (AceCS); angiopoietin-like protein 3 (ANGPTL3); carnitine palmitoyltransferase I (CPT-I); chenodeoxycholic acid (CDCA); cholesterol 7α-hydroxylase (CYP7A1); cholic acid (CA); farnesoid X receptor (FXR); fatty acid synthase (FAS); LDL receptor (LDL-R); liver receptor homolog-1 (LRH-1); liver receptor homolog-1 response element (LRH-1RE); liver X receptor (LXR); liver X receptor response element (LXRRE); long-chain acyl-CoA dehydrogenase (LCAD); malic enzyme (ME); medium-chain acyl-CoA dehydrogenase (MCAD); retinoid X receptor (RXR); short heterodimer partner (SHP); stearoyl-CoA desaturase-1 (SCD-1); triglyceride (TG). Conflict of interest:The authors have declared that no conflict of interest exists. Plasmids. pCMX-SHP was obtained by insertion of a PCR product corresponding to the mouse SHP cDNA into the pCMX vector. pCMX-liver receptor homolog-1 (pCMX-LRH-1) was produced by insertion of a PCR product corresponding to the mouse LRH-1 cDNA into pCMX. The pCMX-LXRα expression vector was as described (10); the pSG5-retinoid X receptor α (pSG5-RXRα) expression vector was a gift of P. Chambon (Institut Clinique de la Souris, Illkirch, France). The SREBP-1c promoter luciferase reporter plasmids were generated by PCR amplification of promoter fragments corresponding to sequences located between -1070 to -51 of the mouse SREBP-1c gene. The PCR product was ligated into the pGL3 basic vector (Promega, Madison, Wisconsin, USA). The reverse primer used for each promoter construct is 5′-CTTCCGCGCCGATTTCACCTG-3′. The different forward primers used for each construct are as follows: pSREBP-1c1070-Luc (5′-ACCCCTCAGACTGTGTGAGT-3′), pSREBP-1c571-Luc (5′-CTA GCTAGATGACCCTGCACCACCAA-3′), pSREBP-1c327-Luc (5′-TTGCCTGTGCGGCAGGGGTTGGGACGA-3′), pSREBP1c276-Luc (5′-CGCGCTGGCGCAGACGCGGTTAAA-3′), and pSREBP-1c151-Luc (5′-CTGCTGATTGGCCATGTGCGCTCA-3′). The primers were tailed with either a KpnI site (forward) or a BglII site (reverse). The LXR response elements in pSREBP-1c324-Luc were mutated for promoter analysis using the Quick Change SiteDirected Mutagenesis Kit (Stratagene, La Jolla, California, USA). All constructs were verified by sequence analysis.Ani...

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Section: Discussionmentioning

confidence: 69%

Section: Introductionmentioning

confidence: 99%

Bile acids lower triglyceride levels via a pathway involving FXR, SHP, and SREBP-1c

Watanabe¹,

Wang²,

Moschetta³

et al. 2004

J. Clin. Invest.

290

324

View full text Add to dashboard Cite

show abstract

“…Although the cause-and-effect relationship of this association has not been clarified, the results of the current study open the possibility that decreased activity of PPAR␣ could be the cause of both hypertriglyceridemia and decreased ileal bile salt absorption. The flux of bile salts through the enterohepatic circulation appears to have a direct effect on hepatic VLDL synthesis because patients administered CDCA exhibit decreased serum triglyceride concentrations (46). Conversely, interruption of the enterohepatic circulation of bile salts with cholestyramine transiently increases serum VLDL-triglyceride levels (47)(48)(49).…”

Section: Discussionmentioning

confidence: 99%

Human Apical Sodium-dependent Bile Salt Transporter Gene (SLC10A2) Is Regulated by the Peroxisome Proliferator-activated Receptor α

Jung¹,

Fried²,

Kullak‐Ublick³

2002

Journal of Biological Chemistry

105

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The apical sodium-dependent bile salt transporter (ASBT/SLC10A2), also called the ileal bile acid transporter, mediates the intestinal absorption of bile salts. The efficiency of this transport process is a determinant of hepatic bile salt synthesis from cholesterol and of serum triglyceride levels. Our aim was to characterize the human ASBT gene promoter with respect to regulatory mechanisms that coordinately affect ASBT expression and hepatic lipid and bile salt metabolism. The minimal construct that confers full promoter activity contains three functional hepatocyte nuclear factor 1␣ (HNF1␣) recognition sites, explaining the dependence of ASBT gene expression upon HNF1␣. A nuclear receptor binding site arranged as a direct hexanucleotide repeat (DR1 motif) is localized ϳ1.6 kb upstream of the transcription initiation site. Constructs containing this element were transactivated by WY14643 and ciprofibrate, ligands of the peroxisome proliferator-activated receptor ␣ (PPAR␣), in Caco2 cells. The DR1 element was shown to bind the PPAR␣/9-cis-retinoic acid receptor heterodimer, and targeted mutagenesis of the DR1 motif abolished PPAR␣ responsiveness. Ciprofibrate treatment of SK-ChA cholangiocytes increased ASBT mRNA levels, suggesting a physiologic role for PPAR␣-mediated ASBT gene regulation. This study identifies PPAR␣ as a novel link between ileal bile salt absorption and hepatic lipid metabolism.

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“…In fact, in dyslipidemic patients, bile acidbinding resins induce the hepatic production of VLDL triglycerides (TGs) [65 -67]. Furthermore, treatment with CDCA, which has been used in the past in patients with cholesterol gallstones, has been shown to reduce plasma TG levels [65,68,69]. The relationship between bile-acid signaling and TG homeostasis has been further highlighted by the observation that Fxr -/-mice have increased hepatic and serum triglyceride levels [8].…”

Section: Bile Acids Regulate Lipid Metabolismmentioning

confidence: 99%

Lipid sensing and lipid sensors

Scotti

Gilardi

Godio

et al. 2007

Cell. Mol. Life Sci.

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The field of bile acids has witnessed an impulse in the last two decades. This has been the result of cloning the genes encoding enzymes of bile acid synthesis and their transporters. There is no doubt that the identification of Farnesoid X Receptor (FXR, NR1H4) as the bile acid receptor has contributed substantially to attract the interest of scientists in this area. When FXR was cloned by Forman et al. [1], farnesol metabolites were initially considered the physiological ligands. After identifying FXR and other nuclear receptors as bile acid sensors [2-4], it has become clear that bile acids are involved in the regulation of lipid and glucose metabolism and that these molecules are eclectic regulators of diverse cellular functions. In this review, we will summarize the current knowledge of the functions regulated by bile acids and how their physiological receptors mediate the signaling underlying numerous cellular responses.

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Chenodeoxycholic Acid and Ursodeoxycholic Acid Effects in Endogenous Hypertriglyceridemias. A Controlled Double‐Blind Trial

Cited by 51 publications

References 15 publications

Bile acids lower triglyceride levels via a pathway involving FXR, SHP, and SREBP-1c

Bile acids lower triglyceride levels via a pathway involving FXR, SHP, and SREBP-1c

Human Apical Sodium-dependent Bile Salt Transporter Gene (SLC10A2) Is Regulated by the Peroxisome Proliferator-activated Receptor α

Lipid sensing and lipid sensors

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