Significant positive association of endotoxemia with histological severity in 237 patients with non‐alcoholic fatty liver disease

Pang, Jesse C.S.; Xu, Weiqi; Zhang, Xiaolang; Wong, Grace Lai–Hung; Chan, Anthony W.H.; Chan, Hung; Tse, Chi‐Shing; Shu, Sally She‐Ting; Choi, Paul Cheung–Lung; Chan, Henry Lik‐Yuen; Yu, Jun; Wong, Vincent Wai‐Sun

doi:10.1111/apt.14119

Cited by 63 publications

(55 citation statements)

References 50 publications

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“…Interestingly, TM6SF2 has been implicated in cholesterol synthesis . In addition, TM6SF2 , but not PNPLA3 , genotypes correlate with endotoxemia . Hence, the lean NAFLD phenotype might be consistent with obesity resistance, in which individuals are still prone to develop steatosis in response to an obesogenic environment (and perhaps a diet enriched in cholesterol), likely by genetic and gut‐driven mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Lean NAFLD: A Distinct Entity Shaped by Differential Metabolic Adaptation

et al. 2020

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Background and Aims Nonalcoholic fatty liver disease (NAFLD) affects a quarter of the adult population. A significant subset of patients are lean, but their underlying pathophysiology is not well understood. Approach and Results We investigated the role of bile acids (BAs) and the gut microbiome in the pathogenesis of lean NAFLD. BA and fibroblast growth factor (FGF) 19 levels (a surrogate for intestinal farnesoid X receptor [FXR] activity), patatin‐like phospholipase domain containing 3 (PNPLA3), and transmembrane 6 superfamily member 2 (TM6SF2) variants, and gut microbiota profiles in lean and nonlean NAFLD were investigated in a cohort of Caucasian patients with biopsy‐proven NAFLD (n = 538), lean healthy controls (n = 30), and experimental murine models. Patients with lean NAFLD had a more favorable metabolic and histological profile compared with those with nonlean NAFLD (P < 0.05 for all). BA levels were significantly higher in NAFLD with advanced compared with earlier stages of liver fibrosis. Patients with lean NAFLD had higher serum secondary BA and FGF19 levels and reduced 7‐alpha‐hydroxy‐4‐cholesten‐3‐one (C4) levels (P < 0.05 for all). These differences were more profound in early compared with advanced stages of fibrosis (P < 0.05 for both). Lean patients demonstrated an altered gut microbiota profile. Similar findings were demonstrated in lean and nonlean murine models of NAFLD. Treating mice with an apical sodium‐dependent BA transporter inhibitor (SC‐435) resulted in marked increases in fgf15, a shift in the BA and microbiota profiles, and improved steatohepatitis in the lean model. Conclusions Differences in metabolic adaptation between patients with lean and nonlean NAFLD, at least in part, explain the pathophysiology and provide options for therapy.

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Section: Discussionmentioning

confidence: 99%

Lean NAFLD: A Distinct Entity Shaped by Differential Metabolic Adaptation

et al. 2020

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“…Studies have demonstrated the successful pharmacological inhibition of hepatic monocyte/macrophage infiltration and amelioration of steatosis and inflammation development by the inhibition of Ccl2 or Cxcl10 , which links hepatocyte lipotoxicity to macrophage‐associated liver inflammation in NASH as a potent chemotactic ligand . There is evidence that the endotoxemia marker Lbp is increased in patients with NASH and this correlates with lobular inflammation, and the knockout of Lbp in mice can decrease indices of liver damage determined by liver histology and serum transaminases . Stat1 serves as a mediator in interferon γ and chemokine expression induced by lipopolysaccharide in macrophages, and the inhibition of Stat1 can inhibit the release of chemokines and suppress the amplification cascade of inflammatory signals .…”

Section: Discussionmentioning

confidence: 99%

“…35 Studies have demonstrated the successful pharmacological inhibition of hepatic monocyte/macrophage infiltration and amelioration of steatosis and inflammation development by the inhibition of Ccl2 or Cxcl10, which links hepatocyte lipotoxicity to macrophage-associated liver inflammation in NASH as a potent chemotactic ligand. 36,37 There is evidence that the endotoxemia marker Lbp is increased in patients with NASH and this correlates with lobular inflammation, 38 There were some limitations to our study. First, TG levels were measured only in the serum, while its accumulation in hepatocytes is actually the main component of hepatic steatosis.…”

Section: Network-based Regulatory Model Of Yzh Liquid On Nashmentioning

confidence: 92%

Effects and therapeutic mechanism of Yinzhihuang on steatohepatitis in rats induced by a high‐fat, high‐cholesterol diet

Zeng

Liu

Xin

et al. 2020

J of Digest Diseases

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Objectives We aimed to investigate the therapeutic mechanism of Yinzhihuang (YZH) liquid, a traditional Chinese medicine mainly composed of extracts of four components, on nonalcoholic steatohepatitis (NASH) induced by a high‐fat, high‐cholesterol diet (HFHCD) in rats. Methods Altogether 30 Sprague‐Dawley rats were randomized into three groups: control, the model group (HFHCD + saline) and the treatment group (HFHCD + YZH). Liver histological features and serum biochemical parameters were assessed by the end of the 16th week. RNA sequencing and protein mass spectrometry detection were performed. The genes and proteins expressed differentially were subjected to KEGG pathway enrichment analysis and included in a network‐based regulatory model. Results The weight, liver and fat indices and serum alanine transaminase, aspartate transaminase and total cholesterol levels of the HFHCD + YZH group were all significantly lower than those of the HFHCD + saline group. Moreover, their hepatic steatosis, ballooning and lobular inflammation were relieved, and 64 hepatic genes and 73 hepatic proteins were found to be reversed in their expression patterns after YZH treatment (P < 0.05). The network‐based regulatory model showed that these deregulated genes and proteins were mainly involved in oxidative phosphorylation, Toll‐like receptor, nucleotide‐binding oligomerization domain‐like receptor, peroxisome proliferator‐activated receptor signaling, nuclear factor‐kappa B tumor necrosis factor signaling pathways and fatty acid metabolism. Conclusion YZH could alleviate NASH in HFHCD‐fed rats by inhibiting lipogenesis, accelerating lipid β‐oxidation, alleviating oxidative stress and relieving necroinflammation in the liver.

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“…NASH is now the most common indication for liver transplant in the Western world. NASH with advanced fibrosis is associated with a faecal microbiome‐derived metagenomic signature 50 and increased endotoxaemia 51 …”

Section: Microbiota In Liver Diseasementioning

confidence: 99%

“…NASH with advanced fibrosis is associated with a faecal microbiome-derived metagenomic signature 50 and increased endotoxaemia. 51 The gut microbiota may also play a role in the variable susceptibility to alcoholic liver disease. The microbiota differs between patients with severe alcoholic hepatitis and those who maintain normal hepatic function despite similar alcohol intake.…”

Section: Microbiota Role In Obesity and The Metabolic Syndromementioning

confidence: 99%

The gut microbiota: cause and cure of gut diseases

White

Bogaerde

Kamm

2018

Medical Journal of Australia

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Summary The gastrointestinal microbiota is emerging as a central factor in the pathogenesis of a range of gastrointestinal and hepatic disorders. Epidemiological studies, and experimental studies in animals and humans, have highlighted a likely causative role of this microbial community in the modern global epidemics of inflammatory bowel disease, non‐alcoholic fatty liver disease, non‐alcoholic steato‐hepatitis, obesity and metabolic syndrome. New techniques for microbial culture and gene sequencing are enabling the identification of specific pathogens and protective organisms in these conditions. Factors that change the microbiota are being defined: dietary pattern, specific foods, food additives in processed food and drinks, such as emulsifiers and non‐sugar sweeteners, and antibiotics. Microbiota changes in early life appear critical to the later development of a range of inflammatory disorders. For many of these conditions, the treatment paradigm will change, at least in part, from immune suppression and drug therapy to treatments that reshape the microbiota or restore its integrity. These treatments include dietary changes, specific microbial manipulation and faecal microbiota transplantation. A dialogue is needed regarding population strategies that target disease prevention. This will include how food is produced, what additives it contains, and how it is processed. Widespread use of antibiotics, from agricultural and veterinary to medicinal settings, needs more attention. At the individual level, microbial profiles may be able to predict who is at risk of disease when subjected to particular environmental influences, and what microbial restoration is needed to minimise risk.

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Significant positive association of endotoxemia with histological severity in 237 patients with non‐alcoholic fatty liver disease

Abstract: Endotoxemia is positively associated with NASH and significant fibrosis. The association between TM6SF2 and endotoxemia warrants further investigations. The findings may shed light on the pathogenesis of NASH and inform a novel treatment target.

Cited by 63 publications

References 50 publications

Lean NAFLD: A Distinct Entity Shaped by Differential Metabolic Adaptation

Lean NAFLD: A Distinct Entity Shaped by Differential Metabolic Adaptation

Effects and therapeutic mechanism of Yinzhihuang on steatohepatitis in rats induced by a high‐fat, high‐cholesterol diet

The gut microbiota: cause and cure of gut diseases

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