A two-hit model of alcoholic liver disease that exhibits rapid, severe fibrosis.
A two-hit model of alcoholic liver disease that exhibits rapid, severe fibrosis.
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DOI：
10.1371/journal.pone.0249316
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发表时间：
2021
期刊：
影响因子：
3.7
通讯作者：
Flaveny CA
中科院分区：
文献类型：
--
作者：
Sengupta M;Abuirqeba S;Kameric A;Cecile-Valfort A;Chatterjee A;Griffett K;Burris TP;Flaveny CA
酒精性肝病（ALD）在男性和女性中分别造成平均50.4%和44.2%的肝病死亡。由于酒精滥用，ALD通常可以通过停止消费来逆转。然而，禁欲计划在减少虐待和生命损失方面的成功有限。因此，ALD仍然是一个重大的临床挑战。需要有效的治疗方法来预防或逆转酒精引起的肝损伤，以补充或取代行为干预。代谢综合征在ALD患者中普遍存在，加速ALD的进展并增加肝病死亡率。遗憾的是，目前ALD的啮齿动物模型不能解释西方饮食对ALD病理学的贡献。为了解决这个问题，我们开发了一种整合西方饮食和酒精影响的ALD啮齿动物模型; Wash饮食模型。我们在这里表明，与单独接受慢性酒精的小鼠相比，WASH饮食，无论是长期还是在小的时间限制性发作中，都会加速ALD病理学，伴有严重的脂肪性肝炎，炎症升高和纤维化增加。我们还验证了我们的Wash饮食模型作为用于测试实验ALD治疗功效的体内系统。反向激动剂SR9238的疗效，先前显示抑制非酒精和酒精诱导的脂肪性肝炎进展，在我们的Wash饮食模型中是保守的。这些发现表明，Wash饮食可能有助于新疗法的体内临床前评估。
Alcoholic liver disease (ALD) is responsible for an average of 50.4% and 44.2%of liver disease deaths among males and females respectively. Driven by alcohol misuse, ALD is often reversible by cessation of consumption. However, abstinence programs can have limited success at curtailing abuse, and the loss of life. ALD, therefore, remains a significant clinical challenge. There is a need for effective treatments that prevent or reverse alcohol-induced liver damage to complement or supplant behavioral interventions. Metabolic syndrome, which is disproportionally prevalent in ALD patients, accelerates the progression of ALD and increases liver disease mortality. Current rodent models of ALD unfortunately do not account for the contribution of the western diet to ALD pathology. To address this, we have developed a rodent model of ALD that integrates the impact of the western diet and alcohol; the WASH-diet model. We show here that the WASH diet, either chronically or in small time-restricted bouts, accelerated ALD pathology with severe steatohepatitis, elevated inflammation and increased fibrosis compared to mice receiving chronic alcohol alone. We also validated our WASH-diet model as an in vivo system for testing the efficacy of experimental ALD treatments. The efficacy of the inverse-agonist SR9238, previously shown to inhibit both non-alcohol and alcohol-induced steatohepatitis progression, was conserved in our WASH-diet model. These findings suggested that the WASH-diet may be useful for in vivo pre-clinical assessment of novel therapies.
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LXR反向激动剂SR9238在非酒精性脂肪性肝炎模型中抑制纤维化。
影响因子：
8.1
作者：
Griffett K;Welch RD;Flaveny CA;Kolar GR;Neuschwander-Tetri BA;Burris TP
通讯作者：
Burris TP
影响因子：
25.7
作者：
Dyson, Jessica;Jaques, Bryan;Reeves, Helen L.
通讯作者：
Reeves, Helen L.
影响因子：
15.9
作者：
Shen, Hong;Jiang, Lin;Rui, Liangyou
通讯作者：
Rui, Liangyou
影响因子：
7.6
作者：
Loomba R;Bettencourt R;Barrett-Connor E
通讯作者：
Barrett-Connor E
影响因子：
2.3
作者：
Brandon-Warner, Elizabeth;Schrum, Laura W.;Schmidt, C. Max;McKillop, Iain H.
通讯作者：
McKillop, Iain H.