Insulin resistance dysregulates CYP7B1 leading to oxysterol accumulation: a pathway for NAFL to NASH transition

Kakiyama, Genta; Marques, Dalila; Martin, Rebecca; Takei, Hiroyuki; Rodríguez‐Agudo, Daniel; LaSalle, Sandra A.; Hashiguchi, Taishi; Li, Xiaoying; Green, Richard; Erickson, Sandra K.; Gil, Gregorio; Fuchs, Michael; Suzuki, Mitsuyoshi; Murai, Tsuyoshi; Nittono, Hiroshi; Hylemon, Phillip B.; Zhou, Huiping; Pandak, William M.

doi:10.1194/jlr.ra120000924

Cited by 34 publications

(51 citation statements)

References 69 publications

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“…We hypothesize that a similar mechanism may be occurring in the intestines, whereby the increased bile acid fecal excretion may be due to reduced enterohepatic circulation regulated by SCT/ASBT in the intestines, but this warrants further studies. Parallel with previous findings, ( 50 ) we demonstrated that Cyp7b1 expression was decreased in WT HFD hepatocytes, whereas Sct or Sctr knockout reverses the expression of Cyp7b1 , which indicates that Sct or Sctr knockout alleviates HFD‐induced liver injury by altering the bile acid pathway.…”

Section: Discussionsupporting

confidence: 90%

Inhibition of Secretin/Secretin Receptor Axis Ameliorates NAFLD Phenotypes

Chen

Kennedy

et al. 2021

Hepatology

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Background and Aims Human NAFLD is characterized at early stages by hepatic steatosis, which may progress to NASH when the liver displays microvesicular steatosis, lobular inflammation, and pericellular fibrosis. The secretin (SCT)/secretin receptor (SCTR) axis promotes biliary senescence and liver fibrosis in cholestatic models through down‐regulation of miR‐125b signaling. We aim to evaluate the effect of disrupting biliary SCT/SCTR/miR‐125b signaling on hepatic steatosis, biliary senescence, and liver fibrosis in NAFLD/NASH. Approach and Results In vivo, 4‐week‐old male wild‐type, Sct−/− and Sctr−/− mice were fed a control diet or high‐fat diet (HFD) for 16 weeks. The expression of SCT/SCTR/miR‐125b axis was measured in human NAFLD/NASH liver samples and HFD mouse livers by immunohistochemistry and quantitative PCR. Biliary/hepatocyte senescence, ductular reaction, and liver angiogenesis were evaluated in mouse liver and human NAFLD/NASH liver samples. miR‐125b target lipogenesis genes in hepatocytes were screened and validated by custom RT2 Profiler PCR array and luciferase assay. Biliary SCT/SCTR expression was increased in human NAFLD/NASH samples and in livers of HFD mice, whereas the expression of miR‐125b was decreased. Biliary/hepatocyte senescence, ductular reaction, and liver angiogenesis were observed in human NAFLD/NASH samples as well as HFD mice, which were decreased in Sct−/− and Sctr−/− HFD mice. Elovl1 is a lipogenesis gene targeted by miR‐125b, and its expression was also decreased in HFD mouse hepatocytes following Sct or Sctr knockout. Bile acid profile in fecal samples have the greatest changes between wild‐type mice and Sct−/−/Sctr−/− mice. Conclusion The biliary SCT/SCTR/miR‐125b axis promotes liver steatosis by up‐regulating lipid biosynthesis gene Elovl1. Targeting the biliary SCT/SCTR/miR‐125b axis may be key for ameliorating phenotypes of human NAFLD/NASH.

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Section: Discussionsupporting

confidence: 90%

Inhibition of Secretin/Secretin Receptor Axis Ameliorates NAFLD Phenotypes

Chen

Kennedy

et al. 2021

Hepatology

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“…In a recent study, Raselli et al pointed towards a non-essential role of CYP7B1 in MAFLD progression, as both hepatic fibrosis and disease activity score were comparable between HFD-fed WT and Cyp7b1 −/− mice [42]. On the contrary, Kakiyama et al provided evidence that, especially under conditions of insulin resistance, CYP7B1 could mediate progression to steatohepatitis, owing to the accumulation of toxic oxysterols that could promote inflammation and liver damage [43]. Recently, it has been shown that thermoneutral housing, a condition of low brown adipose tissue activity and diminished energy expenditure [44], provides a suitable model of exacerbated diet-induced MAFLD in mice [23].…”

Section: Discussionmentioning

confidence: 99%

Oxysterol 7-α Hydroxylase (CYP7B1) Attenuates Metabolic-Associated Fatty Liver Disease in Mice at Thermoneutrality

Evangelakos

Schwinge

Worthmann

et al. 2021

Cells

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Ambient temperature is an important determinant of both the alternative bile acid synthesis pathway controlled by oxysterol 7-α hydroxylase (CYP7B1) and the progression of metabolic-associated fatty liver disease (MAFLD). Here, we investigated whether CYP7B1 is involved in the etiology of MAFLD under conditions of low and high energy expenditure. For this, Cyp7b1−/− and wild type (WT) mice were fed a choline-deficient high-fat diet and housed either at 30 °C (thermoneutrality) or at 22 °C (mild cold). To study disease phenotype and underlying mechanisms, plasma and organ samples were analyzed to determine metabolic parameters, immune cell infiltration by immunohistology and flow cytometry, lipid species including hydroxycholesterols, bile acids and structural lipids. In WT and Cyp7b1−/− mice, thermoneutral housing promoted MAFLD, an effect that was more pronounced in CYP7B1-deficient mice. In these mice, we found higher plasma alanine aminotransferase activity, hyperlipidemia, hepatic accumulation of potentially harmful lipid species, aggravated liver fibrosis, increased inflammation and immune cell infiltration. Bile acids and hydroxycholesterols did not correlate with aggravated MAFLD in Cyp7b1−/− mice housed at thermoneutrality. Notably, an up-regulation of lipoprotein receptors was detected at 22 °C but not at 30 °C in livers of Cyp7b1−/− mice, suggesting that accelerated metabolism of lipoproteins carrying lipotoxic molecules counteracts MAFLD progression.

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“…The serum and liver tissues were processed for bile acid analysis, as described previously [ 19 ]. The processed samples were filtered using Whatman TM Mini-UniPrepTM syringeless filters (0.2 µm PTFE, Cat.…”

Section: Methodsmentioning

confidence: 99%

Berberine Prevents Disease Progression of Nonalcoholic Steatohepatitis through Modulating Multiple Pathways

Wang

Tai

Zhao

et al. 2021

Cells

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The disease progression of nonalcoholic fatty liver disease (NAFLD) from simple steatosis (NAFL) to nonalcoholic steatohepatitis (NASH) is driven by multiple factors. Berberine (BBR) is an ancient Chinese medicine and has various beneficial effects on metabolic diseases, including NAFLD/NASH. However, the underlying mechanisms remain incompletely understood due to the limitation of the NASH animal models used. Methods: A high-fat and high-fructose diet-induced mouse model of NAFLD, the best available preclinical NASH mouse model, was used. RNAseq, histological, and metabolic pathway analyses were used to identify the potential signaling pathways modulated by BBR. LC–MS was used to measure bile acid levels in the serum and liver. The real-time RT-PCR and Western blot analysis were used to validate the RNAseq data. Results: BBR not only significantly reduced hepatic lipid accumulation by modulating fatty acid synthesis and metabolism but also restored the bile acid homeostasis by targeting multiple pathways. In addition, BBR markedly inhibited inflammation by reducing immune cell infiltration and inhibition of neutrophil activation and inflammatory gene expression. Furthermore, BBR was able to inhibit hepatic fibrosis by modulating the expression of multiple genes involved in hepatic stellate cell activation and cholangiocyte proliferation. Consistent with our previous findings, BBR’s beneficial effects are linked with the downregulation of microRNA34a and long noncoding RNA H19, which are two important players in promoting NASH progression and liver fibrosis. Conclusion: BBR is a promising therapeutic agent for NASH by targeting multiple pathways. These results provide a strong foundation for a future clinical investigation.

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Insulin resistance dysregulates CYP7B1 leading to oxysterol accumulation: a pathway for NAFL to NASH transition

Cited by 34 publications

References 69 publications

Inhibition of Secretin/Secretin Receptor Axis Ameliorates NAFLD Phenotypes

Inhibition of Secretin/Secretin Receptor Axis Ameliorates NAFLD Phenotypes

Oxysterol 7-α Hydroxylase (CYP7B1) Attenuates Metabolic-Associated Fatty Liver Disease in Mice at Thermoneutrality

Berberine Prevents Disease Progression of Nonalcoholic Steatohepatitis through Modulating Multiple Pathways

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