Blocking hepatocarcinogenesis by a cytochrome P450 family member with female-preferential expression

Ji, Feiyang; Zhang, Jianjuan; Liu, Niya; Gu, Yuanzhuo; Zhang, Yan; Huang, Peipei; Zhang, Nachuan; Lin, Shengda; Pan, Ran; Meng, Zhuo-Xian; Feng, Xin‐Hua; Roessler, Stephanie; Zheng, Xin; Ji, Junfang

doi:10.1136/gutjnl-2021-326050

Cited by 26 publications

(13 citation statements)

References 48 publications

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“…Cyp7b1 attenuates NAFLD in mice at thermoneutrality (Evangelakos et al, 2021). In addition to BA synthesis, CYP39A1 inhibits the transcriptional activity of c-MYC via its C-terminal region (Ji et al, 2022). Cyp39a1 was highly gene-dosage-dependently down-regulated in both the male and female GR LHet and LKO AS mice ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Liver-specific glucocorticoid action in alcoholic liver disease: study of glucocorticoid receptor knockout and knockin mice

Wang,

2023

Preprint

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BackgroundGlucocorticoids are the only first-line drugs for severe alcoholic hepatitis (AH), with limited efficacy and various side effects on extrahepatic tissues. Liver-targeting glucocorticoid therapy may have multiple advantages over systemic glucocorticoid for AH. The purpose of this study was to determine the role of hepatocellular glucocorticoid receptor (GR) in alcoholic steatosis (AS) and AH.MethodsAS was induced by a high-fat diet plus binge alcohol in adult male and female mice with liver-specific knockout (LKO) and heterozygote of GR. AH was induced by chronic-plus-binge in middle-aged male mice with liver-specific knockin of GR. Changes in hepatic mRNA and protein expression were determined by qPCR and Western blot.ResultsGR LKO aggravated steatosis and decreased hepatic expression and circulating levels of albumin in both genders of AS mice but only increased markers of liver injury in male AS mice. Marked steatosis in GR LKO mice was associated with induction of lipogenic genes and down-regulation of bile acid synthetic genes. Hepatic protein levels of GR, hepatocyte nuclear factor 4α, and phosphorylated STAT3 were gene-dosage-dependently decreased, whereas that of lipogenic ATP citrate lyase was increased in male GR heterozygote and LKO mice. Interestingly, hepatic expression of estrogen receptor α (ERα) was induced, and the essential estrogen-inactivating enzyme sulfotransferase 1E1 was gene-dosage-dependently down-regulated in GR heterozygote and knockout AS mice, which was associated with induction of ERα-target genes. Liver-specific knockin of GR protected against liver injury and steatohepatitis in middle-aged AH mice.ConclusionsHepatocellular GR is important for protection against AS and AH.

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Section: Resultsmentioning

confidence: 99%

Liver-specific glucocorticoid action in alcoholic liver disease: study of glucocorticoid receptor knockout and knockin mice

Wang,

2023

Preprint

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“…Our results have shown no significant correlation between PWY-5913 and significantly different microbes, which indicated that this different pathway uncovered a whole-level difference. Meanwhile, CYP39A1 encoded a member of the cytochrome P450 superfamily of enzymes and played an important role in tumor progression ( Khenjanta et al, 2014 ; Ji et al, 2022 ) and neurodegenerative disorder ( Vishweswaraiah et al, 2022 ). CYP39A1 might affect a variety of microbes and finally show the difference in the PWY-5913 pathways.…”

Section: Discussionmentioning

confidence: 99%

The host genetics affects gut microbiome diversity in Chinese depressed patients

Han

Ji²,

Wang³

et al. 2023

Front. Genet.

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The gut microbiome and host genetics are both associated with major depressive disorder (MDD); however, the molecular mechanisms among the associations are poorly understood, especially in the Asian, Chinese group. Our study applied linear discriminant analysis (LDA) effect size (LEfSe) and genome-wide association analysis in the cohort with both gut sequencing data and genomics data. We reported the different gut microbiota characteristics between MDD and control groups in the Chinese group and further constructed the association between host genetics and the gut microbiome. Actinobacteria and Pseudomonades were found more in the MDD group. We found significant differences in the ACE and Chao indexes of alpha diversity while no discrepancy in beta diversity. We found three associations between host genetics with microbiome features: beta diversity and rs6108 (p = 8.65 × 10–9), Actinobacteria and rs77379751 (p = 8.56 × 10–9), and PWY-5913 and rs1775633082 (p = 4.54 × 10–8). A species of the Romboutsia genus was co-associated with the species of Ruminococcus gnavus in an internetwork through four genes: METTL8, ITGB2, OTULIN, and PROSER3, with a strict threshold (p < 5 × 10–4). Furthermore, our findings suggested that the gut microbiome diversity might affect microRNA expression in the brain and influenced SERPINA5 and other spatially close genes afterward. These findings suggest new linkages between depression and gut microbiome in Asian, Chinese people, which might be mediated by genes and microRNA regulation in space distance.

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“…Cyp39a1 is involved in the alternative bile aid synthesis [ 56 ], which plays a critical role in removing cholesterol and inhibiting the sterol accumulation in the liver [ 57 ]. Moreover, clinical studies showed that patients with hepatocellular carcinomas (HCC) had lower liver Cyp39a1 expression [ 58 , 59 ]. We found that HFD downregulated the expression of Cyp39a1 ; however, the ablation of gut microbiota upregulated the expression of Cyp39a1 .…”

Section: Discussionmentioning

confidence: 99%

Depletion of Gut Microbiota Inhibits Hepatic Lipid Accumulation in High-Fat Diet-Fed Mice

Han

Wang

Zhong

et al. 2022

IJMS

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Dysregulated lipid metabolism is a key pathology in metabolic diseases and the liver is a critical organ for lipid metabolism. The gut microbiota has been shown to regulate hepatic lipid metabolism in the host. However, the underlying mechanism by which the gut microbiota influences hepatic lipid metabolism has not been elucidated. Here, a gut microbiota depletion mouse model was constructed with an antibiotics cocktail (Abx) to study the mechanism through which intestinal microbiota regulates hepatic lipid metabolism in high-fat diet (HFD)-fed mice. Our results showed that the Abx treatment effectively eradicated the gut microbiota in these mice. Microbiota depletion reduced the body weight and fat deposition both in white adipose tissue and liver. In addition, microbiota depletion reduced serum levels of glucose, total cholesterol (TC), low-density lipoproteins (LDL), insulin, and leptin in HFD-fed mice. Importantly, the depletion of gut microbiota in HFD-fed mice inhibited excessive hepatic lipid accumulation. Mechanistically, RNA-seq results revealed that gut microbiota depletion changed the expression of hepatic genes involved in cholesterol and fatty acid metabolism, such as Cd36, Mogat1, Cyp39a1, Abcc3, and Gpat3. Moreover, gut microbiota depletion reduced the abundance of bacteria associated with abnormal metabolism and inflammation, including Lachnospiraceae, Coriobacteriaceae_UCG-002, Enterorhabdus, Faecalibaculum, and Desulfovibrio. Correlation analysis showed that there was strong association between the altered gut microbiota abundance and the serum cholesterol level. This study indicates that gut microbiota ameliorates HFD-induced hepatic lipid metabolic dysfunction, which might be associated with genes participating in cholesterol and fatty acid metabolism in the liver.

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Blocking hepatocarcinogenesis by a cytochrome P450 family member with female-preferential expression

Cited by 26 publications

References 48 publications

Liver-specific glucocorticoid action in alcoholic liver disease: study of glucocorticoid receptor knockout and knockin mice

Liver-specific glucocorticoid action in alcoholic liver disease: study of glucocorticoid receptor knockout and knockin mice

The host genetics affects gut microbiome diversity in Chinese depressed patients

Depletion of Gut Microbiota Inhibits Hepatic Lipid Accumulation in High-Fat Diet-Fed Mice

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