Targeted Delivery of Stk25 Antisense Oligonucleotides to Hepatocytes Protects Mice Against Nonalcoholic Fatty Liver Disease
Targeted Delivery of Stk25 Antisense Oligonucleotides to Hepatocytes Protects Mice Against Nonalcoholic Fatty Liver Disease
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DOI：
10.1016/j.jcmgh.2018.12.004
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发表时间：
2019-01-01
影响因子：
7.2
通讯作者：
Mahlapuu, Margit
中科院分区：
文献类型：
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作者：
Cansby, Emmelie;Nunez-Duran, Esther;Mahlapuu, Margit
背景与目的：非酒精性脂肪性肝病（NAFLD）和非酒精性脂肪性肝炎（NASH）正在成为全球肝脏疾病的主要原因。目前，没有针对NAFLD/NASH的特异性药物治疗，这已被认为是21世纪未满足的主要医疗需求之一。我们最近在遗传小鼠模型、人类细胞系和特征明确的患者队列中的研究发现，丝氨酸/苏氨酸蛋白激酶（STK） 25是肝脏脂质分配和NAFLD/NASH的关键调节因子。在这里，我们研究了肝脏特异性STK25抑制剂对饮食性肥胖小鼠模型中NAFLD发生和进展的代谢益处。方法：我们开发了一种针对Stk25的肝细胞特异性三链n -乙酰半乳糖胺（GalNAc）偶联反义寡核苷酸（ASO），并评估了其对慢性饮食脂质暴露后小鼠NAFLD特征的影响。结果：我们发现，与使用galnac偶联的非靶向ASO治疗的小鼠相比，在肥胖小鼠中全身给予肝细胞靶向的GalNAc-Stk25 ASO有效地改善了肝脏脂肪变性、炎症浸润、肝星状细胞活化、营养纤维化和肝细胞损伤，没有任何全身毒性或局部耐受性问题。我们还观察到Stk25 ASO处理对小鼠高脂肪饮食诱导的肝脏氧化应激的保护作用和线粒体功能的改善。此外，GalNAc-Stk25 ASO抑制肝脏中脂肪生成基因表达和乙酰辅酶a羧化酶蛋白丰度，为肝脏脂肪变性抑制的分子机制提供了新的见解。结论：本研究为肝脏特异性抑制STK25在肥胖背景下的代谢益处提供了体内非临床原理证明，并保证了未来的研究，以解决GalNAc-Stk25 ASO在预防和治疗NAFLD方面的治疗潜力。
BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are emerging as leading causes of liver disease worldwide. Currently, no specific pharmacologic therapy is available for NAFLD/NASH, which has been recognized as one of the major unmet medical needs of the 21st century. Our recent studies in genetic mouse models, human cell lines, and well-characterized patient cohorts have identified serine/threonine protein kinase (STK) 25 as a critical regulator of hepatic lipid partitioning and NAFLD/NASH. Here, we studied the metabolic benefit of liver-specific STK25 inhibitors on NAFLD development and progression in a mouse model of diet-induced obesity.METHODS: We developed a hepatocyte-specific triantennary N-acetylgalactosamine (GalNAc)-conjugated antisense oligonucleotide (ASO) targeting Stk25 and evaluated its effect on NAFLD features in mice after chronic exposure to dietary lipids.RESULTS: We found that systemic administration of hepatocyte-targeting GalNAc-Stk25 ASO in obese mice effectively ameliorated steatosis, inflammatory infiltration, hepatic stellate cell activation, nutritional fibrosis, and hepatocellular damage in the liver compared with mice treated with GalNAc-conjugated nontargeting ASO, without any systemic toxicity or local tolerability concerns. We also observed protection against high-fat-diet-induced hepatic oxidative stress and improved mitochondrial function with Stk25 ASO treatment in mice. Moreover, GalNAc-Stk25 ASO suppressed lipogenic gene expression and acetyl-CoA carboxylase protein abundance in the liver, providing insight into the molecular mechanisms underlying repression of hepatic steatosis.CONCLUSIONS: This study provides in vivo nonclinical proof-of-principle for the metabolic benefit of liver-specific inhibition of STK25 in the context of obesity and warrants future investigations to address the therapeutic potential of GalNAc-Stk25 ASO in the prevention and treatment of NAFLD.