Elobixibat, an ileal bile acid transporter inhibitor, ameliorates non-alcoholic steatohepatitis in mice

Yamauchi, Ryo; Takedatsu, Hidetoshi; Yokoyama, Keiji; Yamauchi, Eri; Kawashima, Motoko; Nagata, Takahiro; Uchida, Yotaro; Kitaguchi, Takanori; Higashi, Tomotaka; Fukuda, Hiromi; Tsuchiya, Naoaki; Takata, Kazuhide; Tanaka, Takashi; Morihara, Daisuke; Takeyama, Yoshifumi; Shakado, Satoshi; Sakisaka, Shotaro; Hirai, Fumihito

doi:10.1007/s12072-020-10107-0

Cited by 13 publications

(2 citation statements)

References 33 publications

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“…An ileal bile acid transporter inhibitor (IBATi) reduces serum BA levels and increase fecal BA concentrations. IBATi reduces proinflammatory factor expression in the liver and attenuates hepatic steatosis, inflammation and fibrosis by improving intestinal dysbiosis in NAFLD model mice ( Matsui et al, 2021 ; Yamauchi et al, 2021 ). An increasing number of drugs that interfere with BA metabolism and BA-related signaling pathways have been suggested to treat metabolism-related diseases, and more studies are needed to clarify their effects and safety in the future.…”

Section: Analysis Of Nafld Treatments Related To Ba Metabolismmentioning

confidence: 99%

The role of bile acid metabolism in the occurrence and development of NAFLD

Bing

2022

Front. Mol. Biosci.

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Non-alcoholic fatty liver disease (NAFLD) has become one of the important causes of cirrhosis and liver cancer, resulting in a huge medical burden worldwide. Currently, effective non-invasive diagnostic indicators and drugs for NAFLD are still lacking. With the development of metabolomics technology, the changes in metabolites during the development of NAFLD have been gradually revealed. Bile acid (BA) is the main endpoint of cholesterol metabolism in the body. In addition, it also acts as a signaling factor to regulate metabolism and inflammation in the body through the farnesyl X receptor and G protein-coupled BA receptor. Studies have shown that BA metabolism is associated with the development of NAFLD, but a large number of animal and clinical studies are still needed. BA homeostasis is maintained through multiple negative feedback loops and the enterohepatic circulation of BA. Recently, treatment of NAFLD by interfering with BA synthesis and metabolism has become a new research direction. Here, we review the changes in BA metabolism and its regulatory mechanisms during the development of NAFLD and describe the potential of studies exploring novel non-invasive diagnostic indicators and therapeutic targets for NAFLD based on BA metabolism.

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Section: Analysis Of Nafld Treatments Related To Ba Metabolismmentioning

confidence: 99%

The role of bile acid metabolism in the occurrence and development of NAFLD

Bing

2022

Front. Mol. Biosci.

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“…Clinical investigation reported that the serum level of BAs is relatively higher in NASH patients compared with healthy controls ( Sydor et al, 2020 ), suggesting that the alteration of the BA pool in the development of NASH. Since IBAT is in charging of the efficient BA reabsorption, IBAT inhibitors that prevent BA accumulation are promising agents in improving NASH ( Yamauchi et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Medicinal Formula Huazhi-Rougan Attenuates Non-Alcoholic Steatohepatitis Through Enhancing Fecal Bile Acid Excretion in Mice

et al. 2022

Front. Pharmacol.

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Huazhi-Rougan (HZRG) formula is a Traditional Chinese medicine prescription, and has been widely used to treat non-alcoholic fatty liver disease (NAFLD) and its progressive form non-alcoholic steatohepatitis (NASH). However, the anti-NASH effects and the underlying mechanisms of HZRG have not yet been characterized. Here we showed that 4-week HZRG treatment alleviated methionine-choline-deficiency (MCD) diet-induced NASH in C57BL/6J mice, as evidenced by the improvement of hepatic steatosis and inflammation, as well as the decrease of serum levels of alanine and aspartate transaminases. Fecal 16S rDNA sequencing indicated that HZRG reduced the enrichment of pathogenic bacteria and increased the abundance of bacteria gena that are involved in bile acid (BA) conversation. The alteration of fecal and serum BA profile suggested that HZRG enhanced fecal BA excretion, and reduced the reabsorption of toxic secondary BA species (LCA, DCA, HCA). We further analyzed the BA receptors and transporters, and found that HZRG inhibited the expression of ileal bile acid transporter, and organic solute transporter subunit β, and increased the expression of intestinal tight junction proteins (ZO-1, Occludin, Claudin-2). The modulation of gut dysbiosis and BA profile, as well as the improvement of the intestinal environment, may contribute to the decrease of the p-65 subunit of NF-κB phosphorylation, liver F4/80 positive macrophages, inflammatory cytokine IL-1β and TNF-α expression. In conclusion, HZRG treatment enhances fecal BA excretion via inhibiting BA transporters, modulates BA profiles, gut dysbiosis as well as the intestinal environment, thus contributing to the beneficial effect of HZRG on NASH mice.

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