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- Liao, Lijun, et al.
(författare)
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Intestinal dysbiosis augments liver disease progression via NLRP3 in a murine model of primary sclerosing cholangitis.
- 2019
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Ingår i: Gut. - : BMJ. - 1468-3288 .- 0017-5749. ; 68:8, s. 1477-92
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Tidskriftsartikel (refereegranskat)abstract
- There is a striking association between human cholestatic liver disease (CLD) and inflammatory bowel disease. However, the functional implications for intestinal microbiota and inflammasome-mediated innate immune response in CLD remain elusive. Here we investigated the functional role of gut-liver crosstalk for CLD in the murine Mdr2 knockout (Mdr2-/-) model resembling human primary sclerosing cholangitis (PSC).Male Mdr2-/-, Mdr2-/- crossed with hepatocyte-specific deletion of caspase-8 (Mdr2-/- /Casp8∆hepa) and wild-type (WT) control mice were housed for 8 or 52weeks, respectively, to characterise the impact of Mdr2 deletion on liver and gut including bile acid and microbiota profiling. To block caspase activation, a pan-caspase inhibitor (IDN-7314) was administered. Finally, the functional role of Mdr2-/- -associated intestinal dysbiosis was studied by microbiota transfer experiments.Mdr2-/- mice displayed an unfavourable intestinal microbiota signature and pronounced NLRP3 inflammasome activation within the gut-liver axis. Intestinal dysbiosis in Mdr2-/- mice prompted intestinal barrier dysfunction and increased bacterial translocation amplifying the hepatic NLRP3-mediated innate immune response. Transfer of Mdr2-/- microbiota into healthy WT control mice induced significant liver injury in recipient mice, highlighting the causal role of intestinal dysbiosis for disease progression. Strikingly, IDN-7314 dampened inflammasome activation, ameliorated liver injury, reversed serum bile acid profile and cholestasis-associated microbiota signature.MDR2-associated cholestasis triggers intestinal dysbiosis. In turn, translocation of endotoxin into the portal vein and subsequent NLRP3 inflammasome activation contribute to higher liver injury. This process does not essentially depend on caspase-8 in hepatocytes, but can be blocked by IDN-7314.
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- Mangge, Harald, et al.
(författare)
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Branched-chain amino acids are associated with cardiometabolic risk profiles found already in lean, overweight and obese young
- 2016
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Ingår i: Journal of Nutritional Biochemistry. - : Elsevier BV. - 0955-2863 .- 1873-4847. ; 32, s. 123-127
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Tidskriftsartikel (refereegranskat)abstract
- Cardiovascular risk is increased in obese subjects. Nevertheless, some overweight and obese remain cardiometabolically healthy (CMH), and normal-weight persons develop cardiovascular disease (CVD). Herein, we investigate the potential of branched-chain amino acids (BCAAs) to identify an increased CVD risk in a cross-sectional study of 666 adults and juveniles (age 25.3 +/- 12.8 years), classified as lean, overweight or obese. Cardiometabolic groups were defined by cutoffs of systolic blood pressure <130 mmHg, diastolic blood pressure<85 mmHg, glucose <125 mg/dl, triglycerides <150 mg/dl, HDL-cholesterol>40 mg/dl (males), HDL-cholesterol>50 mg/dl (females) and HOMA-IR<5. CMH had <= 1 cutoff, and cardiometabolically abnormal (CMA) had >= 2 cutoffs. Amino acids were measured by high-pressure lipid chromatography after precipitation of serum with perchloric acid and derivatization with o-phthalaldehyde. Valine correlated with 5, leucine correlated with 3 and isoleucine correlated with 5 of the cardiac risk classification factors. Valine and leucine were significantly higher in the obese (P<.001, P=.015, respectively), overweight (P<.001, P=.015, respectively) and lean (P=.024, P=.012, respectively) CMA compared to CMH subjects. Isoleucine showed except of the lean group the same results. Taken together, BCAAs, especially valine and leucine, are proposed as a cardiometabolic risk marker independent of body mass index (BMI) category.
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