Dietary cholesterol promotes steatohepatitis related hepatocellular carcinoma through dysregulated metabolism and calcium signaling

Liang, Qiaoyi; Teoh, Narcissus; Xu, Lixia; Pok, Sharon; Li, Xiangchun; Chu, Ellie S.M.; Chiu, Jonathan; Dong, Ling; Arfianti, Arfianti; Haigh, W. Geoffrey; Yeh, Matthew M.; Ioannou, George N.; Sung, Joseph J.Y.; Farrell, Geoffrey C.; Yu, Jun

doi:10.1038/s41467-018-06931-6

Cited by 161 publications

(130 citation statements)

References 64 publications

(68 reference statements)

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“…ITPR1 and ITPR2 are the isoforms principally expressed in normal hepatocytes, ( 19,20 ) although hepatocytes begin to express ITPR3 as well in chronic liver diseases and in liver cancer, where it is responsible for certain pathological effects. ( 21,22 ) Unexpectedly, ITPR3 expression markedly increased in hepatocytes during YF infection (Fig. 1D and Supporting Fig.…”

Section: Resultsmentioning

confidence: 83%

“…Several calcium signaling genes were recently shown to be important in human and mouse samples of HCC caused by nonalcoholic steatohepatitis. Among them, ITPR3 was aberrantly up‐regulated in this disease, ( 21 ) suggesting that this calcium channel could play a role in lipid metabolism. Chronic ITPR3 expression also modulates gene expression, triggering an anti‐apoptotic response in HCC.…”

Section: Discussionmentioning

confidence: 99%

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Molecular Mechanism for Protection Against Liver Failure in Human Yellow Fever Infection

Lemos¹,

França²,

Filho³

et al. 2020

Hepatol Commun

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Yellow fever (YF) is a viral hemorrhagic fever that typically involves the liver. Brazil recently experienced its largest recorded YF outbreak, and the disease was fatal in more than a third of affected individuals, mostly because of acute liver failure. Affected individuals are generally treated only supportively, but during the recent Brazilian outbreak, selected patients were treated with liver transplant. We took advantage of this clinical experience to better characterize the clinical and pathological features of YF‐induced liver failure and to examine the mechanism of hepatocellular injury in YF, to identify targets that would be amenable to therapeutic intervention in preventing progression to liver failure and death. Patients with YF liver failure rapidly developed massive transaminase elevations, with jaundice, coagulopathy, thrombocytopenia, and usually hepatic encephalopathy, along with pathological findings that included microvesicular steatosis and lytic necrosis. Hepatocytes began to express the type 3 isoform of the inositol trisphosphate receptor (ITPR3), an intracellular calcium (Ca2+) channel that is not normally expressed in hepatocytes. Experiments in an animal model, isolated hepatocytes, and liver‐derived cell lines showed that this new expression of ITPR3 was associated with increased nuclear Ca2+ signaling and hepatocyte proliferation, and reduced steatosis and cell death induced by the YF virus. Conclusion: Yellow fever often induces liver failure characterized by massive hepatocellular damage plus steatosis. New expression of ITPR3 also occurs in YF‐infected hepatocytes, which may represent an endogenous protective mechanism that could suggest approaches to treat affected individuals before they progress to liver failure, thereby decreasing the mortality of this disease in a way that does not rely on the costly and limited resource of liver transplantation.

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Section: Resultsmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Molecular Mechanism for Protection Against Liver Failure in Human Yellow Fever Infection

Lemos¹,

França²,

Filho³

et al. 2020

Hepatol Commun

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“…Cholesterol is important for many physiological functions (29–31), and as a triglyceride, cholesterol is also an essential material for yolk formation and egg production. However, high cholesterol intake must be avoided in our diet because excess cholesterol is related to cardiovascular disease and nonalcoholic steatohepatitis which contributing to hepatocellular carcinoma, thus increasing the risk to human health (32–34). Moreover, cholesterol content is used in the evaluation of egg quality in the poultry industry.…”

Section: Discussionmentioning

confidence: 99%

Effects of Fermented Idesia Polycarpa Residues supplementation on laying performance of Laying Quails

Liu

Shu

et al. 2018

Preprint

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L. Tang). Tel: (028) 8541 7281 Abbreviated Title：A new feeding raw material applying on laying quails.ABSTRACT: Idesia polycarpa Maxim. var. vestita Diels (Idesia polycarpa), which is 1 widely distributed in south China, is still underexplored. This study applied Idesia 2 polycarpa defatted fruit (IPF) and Candida utilis to the feed of laying quails using 3 solid-state fermentation. In comparison to the standard diet group, birds fed with 4 mixture of IPF and candida utilis (MIC) showed better production capacity, and the 5 ML group (1% MIC added) achieved the greatest egg mass (9.77 on average; P<0.01) 6 and laying rate (87.7% on average; P<0.01). Compared to the standard diet group, the 7 cholesterol content was lower in both the ML (1% MIC addition groups) and IL (1% 8 IPF addition groups), and 5% MIC added group had higher n-3 polyunsaturated fatty 9 acid content. Furthermore, birds given the MIC dietary supplement showed a thicker 10 jejunum wall than the standard diet group. In addition, the related mRNA expression 11 of SRBEP-1, SREBP-2, ATGL, APOVLDL-II which are involved in the fatty acid and 12 cholesterol biosynthesis suggested that the addition of candida utilis could effectively 13 improve the production capacity of laying quails while decrease the negative effects 14 of IPF. This work also demonstrates how MIC can be applied to improve the 15 production of laying quails. 16 IntroductionIdesia polycarpa (Idesia polycarpa Maxim. var. vestita Diels) is widely 19 distributed in south China, and it is known for its high-quality edible oil, which has a 20 high content of conjugated linoleic acid (CLA). Moreover, the application of Idesia 21 polycarpa oil in biodiesel production has been demonstrated (1, 2). There have been 22 several studies on Idesia polycarpa fruit, including functional research on Idesia 23 polycarpa fruit extraction and studies on the improvement of the extraction process. 24The remarkable antioxidant qualities, anti-skin-aging ability (3) and anti-adipogenic 25 ability (4) of Idesia polycarpa extracts have been demonstrated, and an optimized 26 extraction method has also been established (5). However, reports on the application 27 of Idesia polycarpa fruit for the other purposes are still limited. In this study, we are 28 tried to apply Idesia polycarpa defatted fruit (IPF) in laying quail's breeding, and for 29 purpose of effective use, solid-fermentation was selected. 30From a historical perspective, phytogenic materials fermented with specific 31 microbe are recognized to benefit farm animals and are described as far back as the 32 beginning of the last century (6, 7). Even now, fermentation is still gaining interest 33 because of its important role in the production of quality feed and the utilization of 34 unexploited feed materials (8, 9). Moreover, based on existing studies, the addition of 35 probiotic could effectively decrease anti-nutritive factors and allergenic proteins (10, 36 11). Furthermore, fermented feed represents a plausible alternative to traditional 37 anti...

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“…For example, APOE, which has been associated with modulation of total cholesterol 34 [28][29][30][31] supporting their links with cholesterol. b) ACSM5 pairs as an eGene with rs11647589, rs6497490, and rs1394678, which were associated with 3-phenylpropionate, X-11478 (an unknown metabolite), and indolepropionate respectively.…”

Section: Metabolite-associated Snps Mark Eqtlsmentioning

confidence: 93%

Reconstructing the blood metabolome and genotype using long-range chromatin interactions

Fadason

Schierding

Kolbenev

et al. 2019

Preprint

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AbstractThe mechanisms of metabolism comprise a large number of biochemical pathways with a myriad of poorly characterised genetic influences. In this study, we perform a systematic integration of chromatin interaction (Hi-C), expression quantitative trait loci (eQTL), gene ontology, drug interaction, and literature-supported connections to deconvolute the genetic regulatory influences of 145 blood metabolite-associated single nucleotide polymorphisms (SNPs). We identify 577 genes that are regulated via chromatin looping to 130 distal and proximal SNPs across 48 different human tissues. The affected genes are enriched in categories that include metabolism, enzymes, plasma proteins, disease development, and potential drug targets. These novel SNP-gene-metabolite associations are a valuable resource for understanding the molecular mechanisms guiding pathologic metabolite levels in human tissues, and for further investigation into disease diagnosis and therapy.

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Dietary cholesterol promotes steatohepatitis related hepatocellular carcinoma through dysregulated metabolism and calcium signaling

Cited by 161 publications

References 64 publications

Molecular Mechanism for Protection Against Liver Failure in Human Yellow Fever Infection

Molecular Mechanism for Protection Against Liver Failure in Human Yellow Fever Infection

Effects of Fermented Idesia Polycarpa Residues supplementation on laying performance of Laying Quails

Reconstructing the blood metabolome and genotype using long-range chromatin interactions

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