Faculty Opinions recommendation of Farnesoid X receptor activation increases reverse cholesterol transport by modulating bile acid composition and cholesterol absorption in mice.

Cholesterol homoeostasis is the result of the fine tuning between intake and disposal of this molecule. High levels of cholesterol in the blood are detrimental as they may lead to excessive accumulation in vessel walls, a condition predisposing to the development of atherosclerotic lesions. Cholesterol is removed from the vessel wall and transported to the liver through a process called reverse cholesterol transport. Nuclear receptors are among the most important transcription factors regulating genes involved in different steps of reverse cholesterol transport. Here, we discuss the role of the nuclear receptors LXR (liver X receptor) and HNF-4α (hepatocyte nuclear factor-4α) in different steps of reverse cholesterol transport. LXR controls the transcription of crucial genes in cholesterol efflux from macrophages and its transport to the liver, such as ABCA1 (ATP binding cassette A1), CYP27A1 (sterol 27-hydroxylase), CLA-1 (scavenger receptor type B1) and apolipoprotein E. Some oxysterols present in oxidized low-density lipoproteins and proinflammatory cytokines modulate the activity of LXR by antagonizing the effect of activators of this receptor, thus contributing to cholesterol accumulation in macrophages. Bile acid synthesis, which represents the final step of reverse cholesterol transport, is transcriptionally regulated by several nuclear receptors at the level of the liver-specific cytochrome P450 cholesterol 7α-hydroxylase (CYP7A1), the rate-limiting enzyme of this metabolic pathway. Bile acids returning to the liver through the enterohepatic circulation down-regulate CYP7A1 transcription via the bile acid sensors farnesoid X receptor and HNF-4α. Based on this evidence, these nuclear receptors are candidate targets of new drugs for the treatment and prevention of atherosclerotic disease.

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Arbutin Alleviates the Liver Injury of α-Naphthylisothiocyanate-induced Cholestasis Through Farnesoid X Receptor Activation

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.758632 ◽

2021 ◽

Vol 9 ◽

Author(s):

Peijie Wu ◽

Ling Qiao ◽

Han Yu ◽

Hui Ming ◽

Chao Liu ◽

...

Keyword(s):

Bile Acid ◽

Liver Injury ◽

Protective Effect ◽

Bile Acids ◽

Liver Toxicity ◽

Enterohepatic Circulation ◽

Receptor Activation ◽

Farnesoid X Receptor ◽

Bile Acid Metabolism ◽

Cholestatic Diseases

Cholestasis is a kind of stressful syndrome along with liver toxicity, which has been demonstrated to be related to fibrosis, cirrhosis, even cholangiocellular or hepatocellular carcinomas. Cholestasis usually caused by the dysregulated metabolism of bile acids that possess high cellular toxicity and synthesized by cholesterol in the liver to undergo enterohepatic circulation. In cholestasis, the accumulation of bile acids in the liver causes biliary and hepatocyte injury, oxidative stress, and inflammation. The farnesoid X receptor (FXR) is regarded as a bile acid–activated receptor that regulates a network of genes involved in bile acid metabolism, providing a new therapeutic target to treat cholestatic diseases. Arbutin is a glycosylated hydroquinone isolated from medicinal plants in the genus Arctostaphylos, which has a variety of potentially pharmacological properties, such as anti-inflammatory, antihyperlipidemic, antiviral, antihyperglycemic, and antioxidant activity. However, the mechanistic contributions of arbutin to alleviate liver injury of cholestasis, especially its role on bile acid homeostasis via nuclear receptors, have not been fully elucidated. In this study, we demonstrate that arbutin has a protective effect on α-naphthylisothiocyanate–induced cholestasis via upregulation of the levels of FXR and downstream enzymes associated with bile acid homeostasis such as Bsep, Ntcp, and Sult2a1, as well as Ugt1a1. Furthermore, the regulation of these functional proteins related to bile acid homeostasis by arbutin could be alleviated by FXR silencing in L-02 cells. In conclusion, a protective effect could be supported by arbutin to alleviate ANIT-induced cholestatic liver toxicity, which was partly through the FXR pathway, suggesting arbutin may be a potential chemical molecule for the cholestatic disease.

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Triacylglycerol and cholesterol transport during absorption of glycerol trioleate vs. glycerol trielaidate

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.1996.270.2.g268 ◽

1996 ◽

Vol 270 (2) ◽

pp. G268-G276

Author(s):

T. J. Kalogeris ◽

L. Gray ◽

Y. Y. Yeh ◽

P. Tso

Keyword(s):

Fatty Acid Composition ◽

Fatty Acid ◽

Intestinal Absorption ◽

Acid Composition ◽

Trans Fatty Acid ◽

Cholesterol Absorption ◽

Lymphatic Transport ◽

Cholesterol Transport ◽

Lipid Emulsions ◽

Intestinal Lymph

We used conscious, chronic lymph-fistula rats to compare intestinal lymphatic transport of glycerol trioleate (TO) vs. glycerol trielaidate (TE) and to determine the effect of TO vs. TE on absorption and transport of cholesterol. Rats were implanted with intestinal lymph fistulas and duodenal cannulas and then given intraduodenal infusions of lipid emulsions containing purified TO or TE (40 mumol/h) and cholesterol (7.8 mumol/h + 2 microCi [14C]cholesterol). Lymph samples were collected at 0, 2, 4, 5, 6, 7, and 8 h after the start of lipid infusion. Lymphatic output and luminal and gut wall recovery of radioactive lipid at 8 h were quantified. Triacylglycerol (TG) fatty acid isomers did not affect lymphatic output of TG; lymph TG fatty acid composition and output reflected infusate composition. Lymphatic output of cholesterol (mass and radioactivity) did not differ between groups; luminal and gut wall recovery of [14C]cholesterol was also similar between groups. Similar lymphatic transport of TG and cholesterol between triolein- and trielaidin-infused rats was maintained for up to 16 h after the cessation of an infused lipid load. These results indicate that TO and TE are transported into lymph similarly, and that cholesterol absorption and transport are similar irrespective of whether TO or TE is the TG source. The data suggest that trans fatty acid-induced hypercholesterolemia is not due to altered intestinal absorption and transport of cholesterol.

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Cholesterol Absorption From the Intestine Is a Major Determinant of Reverse Cholesterol Transport From Peripheral Tissue Macrophages

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvbaha.108.165803 ◽

2008 ◽

Vol 28 (7) ◽

pp. 1296-1297 ◽

Cited By ~ 47

Author(s):

Ephraim Sehayek ◽

Stanley L. Hazen

Keyword(s):

Reverse Cholesterol Transport ◽

Cholesterol Absorption ◽

Major Determinant ◽

Peripheral Tissue ◽

Cholesterol Transport

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Liver X receptor activation promotes macrophage-to-feces reverse cholesterol transport in a dyslipidemic hamster model

The Journal of Lipid Research ◽

10.1194/jlr.m001552 ◽

2009 ◽

Vol 51 (4) ◽

pp. 763-770 ◽

Cited By ~ 27

Author(s):

François Briand ◽

Morgan Tréguier ◽

Agnès André ◽

Didier Grillot ◽

Marc Issandou ◽

...

Keyword(s):

Reverse Cholesterol Transport ◽

Receptor Activation ◽

Liver X Receptor ◽

Cholesterol Transport ◽

Hamster Model

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Disodium ascorbyl phytostanol phosphate (FM-VP4), a modified phytostanol, is a highly active hypocholesterolaemic agent that affects the enterohepatic circulation of both cholesterol and bile acids in mice

British Journal Of Nutrition ◽

10.1017/s0007114509991656 ◽

2009 ◽

Vol 103 (2) ◽

pp. 153-160 ◽

Cited By ~ 11

Author(s):

J. Méndez-González ◽

S. Süren-Castillo ◽

L. Calpe-Berdiel ◽

N. Rotllan ◽

M. Vázquez-Carrera ◽

...

Keyword(s):

Bile Acid ◽

Target Genes ◽

Enterohepatic Circulation ◽

Acid Output ◽

Cholesterol Absorption ◽

Cholesterol Homeostasis ◽

Farnesoid X Receptor ◽

Liver Cholesterol ◽

Bile Acid Metabolism ◽

Intestinal Cholesterol Absorption

Disodium ascorbyl phytostanol phosphate (FM-VP4) is a synthetic compound derived from sitostanol and campestanol that has proved to be efficient as a cholesterol-lowering therapy in mice and human subjects. However, the mechanism of action of FM-VP4 remains unknown. The present study tests the ability of FM-VP4 to alter intestinal and liver cholesterol homeostasis in mice. Female C57BL/6J mice were fed either a control chow or a 2 % FM-VP4-enriched diet for 4 weeks. FM-VP4 reduced the in vivo net intestinal cholesterol absorption and plasma and liver cholesterol concentrations by 2·2-, 1·5- and 1·6-fold, respectively, compared with control mice. Furthermore, FM-VP4 also showed an impact on bile acid homeostasis. In FM-VP4 mice, liver and intestinal bile acid content was increased by 1·3- and 2·3-fold, respectively, whereas faecal bile acid output was 3·3-fold lower. FM-VP4 also increased the intestinal absorption of orally administered [3H]taurocholic acid to small intestine in vivo. Inhibition of intestinal cholesterol absorption by FM-VP4 was not mediated via transcriptional increases in intestine liver X receptor (LXR)-α, adenosine triphosphate-binding cassette transporter (ABC)-A1, ABCG5/G8 nor to decreases in intestinal Niemann-Pick C1-like 1 (NPC1L1) expression. In contrast, FM-VP4 up-regulated liver LXRα, ABCA1, ABCG5, scavenger receptor class BI (SR-BI) and hydroxymethylglutaryl coenzyme A reductase (HMGCoA-R) gene expression, whereas it down-regulated several farnesoid X receptor (FXR)-target genes such as cytochrome P450 family 7 subfamily A polypeptide 1 (CYP7A1) and Na+/taurocholate co-transporter polypeptide (NTCP). In conclusion, FM-VP4 reduced intestinal cholesterol absorption, plasma and liver cholesterol and affected bile acid homeostasis by inducing bile acid intestinal reabsorption and changed the liver expression of genes that play an essential role in cholesterol homeostasis. This is the first phytosterol or stanol that affects bile acid metabolism and lowers plasma cholesterol levels in normocholesterolaemic mice.

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Bile Acid Sequestrant, Sevelamer Ameliorates Hepatic Fibrosis with Reduced Overload of Endogenous Lipopolysaccharide in Experimental Nonalcoholic Steatohepatitis

Microorganisms ◽

10.3390/microorganisms8060925 ◽

2020 ◽

Vol 8 (6) ◽

pp. 925 ◽

Cited By ~ 2

Author(s):

Yuki Tsuji ◽

Kosuke Kaji ◽

Mitsuteru Kitade ◽

Daisuke Kaya ◽

Koh Kitagawa ◽

...

Keyword(s):

Bile Acid ◽

Hepatic Fibrosis ◽

Nonalcoholic Steatohepatitis ◽

Receptor Activation ◽

Farnesoid X Receptor ◽

Bile Acid Sequestrant ◽

Intestinal Lumen ◽

Fecal Excretion ◽

Clinical Issue ◽

Α Diversity

Despite the use of various pharmacotherapeutic strategies, fibrosis due to nonalcoholic steatohepatitis (NASH) remains an unsatisfied clinical issue. We investigated the effect of sevelamer, a hydrophilic bile acid sequestrant, on hepatic fibrosis in a murine NASH model. Male C57BL/6J mice were fed a choline-deficient, L-amino acid-defined, high-fat (CDHF) diet for 12 weeks with or without orally administered sevelamer hydrochloride (2% per diet weight). Histological and biochemical analyses revealed that sevelamer prevented hepatic steatosis, macrophage infiltration, and pericellular fibrosis in CDHF-fed mice. Sevelamer reduced the portal levels of total bile acid and inhibited both hepatic and intestinal farnesoid X receptor activation. Gut microbiome analysis demonstrated that sevelamer improved a lower α-diversity and prevented decreases in Lactobacillaceae and Clostridiaceae as well as increases in Desulfovibrionaceae and Enterobacteriaceae in the CDHF-fed mice. Additionally, sevelamer bound to lipopolysaccharide (LPS) in the intestinal lumen and promoted its fecal excretion. Consequently, the sevelamer treatment restored the tight intestinal junction proteins and reduced the portal LPS levels, leading to the suppression of hepatic toll-like receptor 4 signaling pathway. Furthermore, sevelamer inhibited the LPS-mediated induction of fibrogenic activity in human hepatic stellate cells in vitro. Collectively, sevelamer inhibited the development of murine steatohepatitis by reducing hepatic LPS overload.

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