The Department of Pharmacology and Physiology, Saint Louis University School of Medicine, Saint Louis, MO, United States of America.
Center for Clinical Pharmacology at Washington University Saint Louis and The Saint Louis College of Pharmacy, Saint Louis, MO, United States of America.
PLoS One. 2021 Mar 26;16(3):e0249316. doi: 10.1371/journal.pone.0249316. eCollection 2021.
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.
酒精性肝病（ALD）分别导致男性和女性中平均 50.4%和 44.2%的肝病死亡。由于酒精滥用，ALD 通过停止饮酒通常是可以逆转的。然而，禁欲计划在遏制滥用和减少死亡方面可能收效有限。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，以补充或替代行为干预。代谢综合征在 ALD 患者中比例过高，会加速 ALD 的进展并增加肝病死亡率。不幸的是，目前用于 ALD 的啮齿动物模型没有考虑到西方饮食对 ALD 病理的贡献。为了解决这个问题，我们开发了一种将西方饮食和酒精的影响结合在一起的 ALD 啮齿动物模型；WASH 饮食模型。我们在这里表明，与仅接受慢性酒精的小鼠相比，WASH 饮食无论是慢性的还是在小的限时发作中，都会加速 ALD 病理，导致严重的脂肪性肝炎、炎症升高和纤维化增加。我们还验证了我们的 WASH 饮食模型作为一种体内系统，用于测试实验性 ALD 治疗的疗效。先前显示抑制非酒精和酒精引起的脂肪性肝炎进展的反向激动剂 SR9238 在我们的 WASH 饮食模型中仍然有效。这些发现表明，WASH 饮食可能有助于新型治疗方法的体内临床前评估。
