Haczeyni Fahrettin, Poekes Laurence, Wang Hans, Mridha Auvro R, Barn Vanessa, Geoffrey Haigh W, Ioannou George N, Yeh Matthew M, Leclercq Isabelle A, Teoh Narcissus C, Farrell Geoffrey C
Liver Research Group, Australian National University Medical School at the Canberra Hospital, Canberra, Australian Capital Territory, Australia.
Laboratory of Hepato-Gastroenterology, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium.
Obesity (Silver Spring). 2017 Jan;25(1):155-165. doi: 10.1002/oby.21701. Epub 2016 Nov 2.
Nonalcoholic steatohepatitis (NASH) is the outcome of interactions between overnutrition, energy metabolism, and adipose function. Obeticholic acid (OCA) improves steatosis in patients but for unknown reasons does not resolve NASH pathology. This study therefore investigated OCA effects in Wt mice, which develop obesity with atherogenic dietary feeding, and appetite-dysregulated, Alms1 mutant foz/foz mice fed the same diet, which develop metabolic obesity and diabetes.
OCA (1 mg/kg) was administered orally to female foz/foz mice and Wt littermates from weaning until 28 weeks. Adipose indices, glucose tolerance, and fatty liver pathology were studied. Experiments were repeated with OCA 10 mg/kg.
OCA reduced body weight and hepatic lipids and improved glucose disposal only in Wt mice. OCA limited Wt adipose expansion, altered morphometry in favor of small adipocytes, enhanced expression of genes indicating adipose browning, and reduced crown-like structure number in visceral adipose tissue. foz/foz mice showed more crown-like structures in all compartments; OCA failed to alter adipose morphometry, browning, inflammation, or improve NASH severity, even at 10 mg/kg.
OCA improved adipose indices, glucose tolerance, and steatosis in a milder metabolic phenotype but failed to improve these factors in morbidly obese diabetic mice. These results help explain OCA's limited efficacy to reverse human NASH.
非酒精性脂肪性肝炎（NASH）是营养过剩、能量代谢和脂肪功能相互作用的结果。奥贝胆酸（OCA）可改善患者的脂肪变性，但原因不明，无法解决NASH的病理问题。因此，本研究调查了OCA对野生型（Wt）小鼠的影响，这些小鼠通过致动脉粥样硬化饮食喂养而肥胖，以及食欲失调的Alms1突变型foz/foz小鼠，它们在喂食相同饮食后会发展为代谢性肥胖和糖尿病。
从断奶到28周，对雌性foz/foz小鼠和野生型同窝小鼠口服给予OCA（1毫克/千克）。研究了脂肪指数、葡萄糖耐量和脂肪肝病理。用10毫克/千克的OCA重复实验。
OCA仅在野生型小鼠中降低了体重和肝脏脂质，并改善了葡萄糖代谢。OCA限制了野生型小鼠的脂肪扩张，改变了形态测量结果，有利于小脂肪细胞，增强了表明脂肪褐变的基因表达，并减少了内脏脂肪组织中的冠状结构数量。在所有区域中，foz/foz小鼠显示出更多的冠状结构；即使在10毫克/千克时，OCA也未能改变脂肪形态、褐变、炎症或改善NASH的严重程度。
OCA在较轻的代谢表型中改善了脂肪指数、葡萄糖耐量和脂肪变性，但在病态肥胖的糖尿病小鼠中未能改善这些因素。这些结果有助于解释OCA逆转人类NASH的疗效有限的原因。
