National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, United States.
Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI, United States.
J Hepatol. 2017 Oct;67(4):809-817. doi: 10.1016/j.jhep.2017.06.008. Epub 2017 Jun 21.
BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) is the most common form of liver disease. Activation of hedgehog (Hh) signaling has been implicated in the progression of NAFLD and proposed as a therapeutic target; however, the effects of Hh signaling inhibition have not been studied in humans with germline mutations that affect this pathway.
Patients with holoprosencephaly (HPE), a disorder associated with germline mutations disrupting Sonic hedgehog (SHH) signaling, were clinically evaluated for NAFLD. A combined mouse model of Hh signaling attenuation (Gli2 heterozygous null: Gli2) and diet-induced NAFLD was used to examine aspects of NAFLD and hepatic gene expression profiles, including molecular markers of hepatic fibrosis and inflammation.
Patients with HPE had a higher prevalence of liver steatosis compared to the general population, independent of obesity. Exposure of Gli2 mice to fatty liver-inducing diets resulted in increased liver steatosis compared to wild-type mice. Similar to humans, this effect was independent of obesity in the mutant mice and was associated with decreased expression of pro-fibrotic and pro-inflammatory genes, and increased expression of PPARγ, a potent anti-fibrogenic and anti-inflammatory regulator. Interestingly, tumor suppressors p53 and p16INK4 were found to be downregulated in the Gli2 mice exposed to a high-fat diet.
Our results indicate that germline mutations disrupting Hh signaling promotes liver steatosis, independent of obesity, with reduced fibrosis. While Hh signaling inhibition has been associated with a better NAFLD prognosis, further studies are required to evaluate the long-term effects of mutations affecting this pathway. Lay summary: Non-alcoholic fatty liver disease (NAFLD) is characterized by excess fat deposition in the liver predominantly due to high calorie intake and a sedentary lifestyle. NAFLD progression is usually accompanied by activation of the Sonic hedgehog (SHH) pathway leading to fibrous buildup (scar tissue) and inflammation of the liver tissue. For the first time patients with holoprosencephaly, a disease caused by SHH signaling mutations, are shown to have increased liver steatosis independent of obesity. This observation was recapitulated in a mouse model of attenuated SHH signaling that also showed increased liver steatosis but with decreased fibrosis and inflammation. While SHH inhibition is associated with a good NAFLD prognosis, this increase in liver fat accumulation in the context of SHH signaling inhibition must be studied prospectively to evaluate its long-term effects, especially in individuals with Western-type dietary habits.
非酒精性脂肪性肝病（NAFLD）是最常见的肝脏疾病。 hedgehog（Hh）信号的激活与 NAFLD 的进展有关，并被提议作为治疗靶点；然而，在具有影响该途径的种系突变的人类中，尚未研究 Hh 信号抑制的影响。
对患有前脑无裂畸形（HPE）的患者进行临床评估，HPE 是一种与 Sonic hedgehog（SHH）信号传导中断的种系突变相关的疾病。使用 Hedgehog 信号衰减（Gli2 杂合子缺失：Gli2）和饮食诱导的 NAFLD 的组合小鼠模型来检查 NAFLD 和肝基因表达谱的各个方面，包括肝纤维化和炎症的分子标志物。
与普通人群相比，患有 HPE 的患者肝脏脂肪变性的患病率更高，而与肥胖无关。与野生型小鼠相比，Gli2 小鼠暴露于诱导肝脏脂肪变性的饮食中会导致肝脏脂肪变性增加。与人类相似，这种作用在突变小鼠中与肥胖无关，与促纤维化和促炎基因的表达减少以及 PPARγ（一种有效的抗纤维化和抗炎调节剂）的表达增加有关。有趣的是，在高脂肪饮食暴露的 Gli2 小鼠中发现肿瘤抑制因子 p53 和 p16INK4 的表达下调。
我们的研究结果表明，破坏 Hedgehog 信号传导的种系突变促进肝脏脂肪变性，与肥胖无关，纤维化减少。虽然 Hedgehog 信号抑制与更好的 NAFLD 预后相关，但需要进一步研究来评估影响该途径的突变的长期影响。
非酒精性脂肪性肝病（NAFLD）的特征是肝脏中脂肪的过度堆积，主要是由于高热量摄入和久坐不动的生活方式。NAFLD 的进展通常伴随着 Sonic hedgehog（SHH）通路的激活，导致纤维组织形成（疤痕组织）和肝组织炎症。首次显示患有前脑无裂畸形的患者（一种由 SHH 信号突变引起的疾病）肝脏脂肪变性增加，与肥胖无关。在 Hedgehog 信号减弱的小鼠模型中也观察到这种观察结果，该模型也显示肝脏脂肪变性增加，但纤维化和炎症减少。虽然 SHH 抑制与良好的 NAFLD 预后相关，但必须前瞻性研究 SHH 信号抑制背景下肝脏脂肪积累的增加，以评估其长期影响，特别是在具有西方饮食习惯的个体中。
