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. METHODS 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. RESULTS 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. CONCLUSIONS 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.

中文翻译：

---

人类生殖系刺猬通路突变易患脂肪肝

背景和目的 非酒精性脂肪性肝病 (NAFLD) 是最常见的肝脏疾病。刺猬 (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，尚未在具有影响该途径的种系突变的人类中研究 Hh 信号抑制的影响。方法 对患有全前脑畸形 (HPE) 的患者进行 NAFLD 的临床评估，HPE 是一种与破坏声波刺猬 (SHH) 信号传导的种系突变相关的疾病。Hh 信号衰减（Gli2 杂合无效：Gli2+/-）和饮食诱导的 NAFLD 的组合小鼠模型用于检查 NAFLD 和肝脏基因表达谱的各个方面，包括肝纤维化和炎症的分子标记。结果与普通人群相比，HPE 患者肝脂肪变性的患病率更高，与肥胖无关。与野生型小鼠相比，Gli2+/- 小鼠暴露于诱导脂肪肝的饮食导致肝脏脂肪变性增加。与人类相似，这种效应与突变小鼠的肥胖无关，并且与促纤维化和促炎基因的表达降低以及 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，发现肿瘤抑制因子 p53 和 p16INK4 在暴露于高脂肪饮食的 Gli2+/- 小鼠中被下调。结论 我们的结果表明，破坏 Hh 信号的种系突变促进了肝脂肪变性，与肥胖无关，纤维化减少。虽然 Hh 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。总结：非酒精性脂肪性肝病 (NAFLD) 的特征是肝脏中过多的脂肪沉积，主要是由于高热量摄入和久坐不动的生活方式。NAFLD 进展通常伴随着 Sonic Hedgehog (SHH) 通路的激活，导致纤维堆积（疤痕组织）和肝组织炎症。首次证明全前脑畸形（一种由 SHH 信号突变引起的疾病）患者的肝脏脂肪变性增加，而与肥胖无关。这一观察结果在 SHH 信号减弱的小鼠模型中得到重现，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，但必须前瞻性地研究这种在 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，尤其是在具有西方饮食习惯的个体中。