Niacin Ameliorates Hepatic Steatosis by Inhibiting De Novo Lipogenesis Via a GPR109A-Mediated PKC-ERK1/2-AMPK Signaling Pathway in C57BL/6 Mice Fed a High-Fat Diet
Niacin Ameliorates Hepatic Steatosis by Inhibiting De Novo Lipogenesis Via a GPR109A-Mediated PKC-ERK1/2-AMPK Signaling Pathway in C57BL/6 Mice Fed a High-Fat Diet
复制标题
烟酸通过 GPR109A 介导的 PKC-ERK1/2-AMPK 信号通路抑制高脂饮食 C57BL/6 小鼠的从头脂肪生成，从而改善肝脏脂肪变性。
DOI：
10.1093/jn/nxz303
复制
发表时间：
2020-04-01
影响因子：
4.2
通讯作者：
Zhou, Naiming
中科院分区：
文献类型：
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作者：
Ye, Lingyan;Cao, Zheng;Zhou, Naiming
背景
非酒精性脂肪性肝病(NAFLD)是世界上最常见的肝病。肝脏新生脂肪生成(DNL)被认为与NAFLD的发病有关。最近的研究表明，烟酸(NA)通过Gpr109a调节肝脏DNL。然而，潜在的机制在很大程度上仍不清楚。
目标
本研究旨在阐明Gpr109a抑制肝脏DNL的潜在分子机制。
方法
C57BL/6野生型(WT)和Gpr109a基因敲除(KO)小鼠(雄性，5周龄)先喂饲高脂饲料(60%脂肪能量)6wk，建立饮食诱导的肥胖模型。随后，在接下来的8~9wk，随机分为4组：WT小鼠口服水[WT+VE]、WT小鼠口服NA(50 mm，溶于水)(WT+VNA)、KO小鼠口服水(KO+VE)、KO小鼠口服NA(50 Mm)(KO+VE)。在HepG2细胞中研究了其作用机制。检测体成分、肝脏组织学、肝功能的生物标志物、脂质蓄积和HepG2细胞中的脂质合成信号。
结果
激活后，Gpr109a明显预防肥胖和肝脏脂肪变性(P<；n0.05)。WT+NA组大鼠肝组织肿瘤坏死因子-α浓度约为WT+VE组的50%(P<0.05)。西药+VE组血清丙氨酸转氨酶和天冬氨酸转氨酶活性分别比西药+VE组低26.7%和53.5%(P<0.05)。在HepG2细胞中，Gpr109a的激活通过蛋白激酶C-细胞外信号调节激酶-1/2-AMP激活的蛋白激酶信号通路显著抑制油酸诱导的脂质蓄积。
结论
NA通过Gpr109a介导的信号通路抑制C57BL/6小鼠的肝脏脂肪生成，这与在HepG2细胞中的机制研究一致，表明其具有治疗NAFLD和其他脂肪肝疾病的潜力。
BACKGROUND
Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in the world. Hepatic de novo lipogenesis (DNL) has been suggested to contribute to the pathogenesis of NAFLD. Recent studies have demonstrated that niacin (NA) modulates hepatic DNL through GPR109A. However, the underlying mechanism remains largely unknown.
OBJECTIVES
This study aims to elucidate the potential molecular mechanism by which GPR109A inhibits hepatic DNL.
METHODS
C57BL/6 wild-type (WT) and Gpr109a knockout (KO) mice (male, 5 wk old) were fed a high-fat diet (60% energy from fat) firstly for 6 wk to generate a diet-induced obese model. Subsequently, they were randomly divided into 4 groups for the next 8-9 wk: WT mice with oral water [WT + vehile (VE)], WT mice with oral NA (50 mM, dissolved in water) (WT + NA), KO mice with oral water (KO + VE), and KO mice with oral NA (50 mM) (KO + NA). Mechanisms were examined in HepG2 cells. Body composition, liver histology, biomarkers of hepatic function, lipid accumulation, and lipid synthesis signals in HepG2 cells were measured.
RESULTS
Upon activation, GPR109A apparently protected against obesity and hepatic steatosis (P < 0.05). The concentrations of hepatic Tnf-α in the WT + NA group were about 50% of those in the WT + VE group (P < 0.05). The activities of serum alanine transaminase and aspartate transaminase were 26.7% and 53.5% lower in the WT + NA group than in the WT + VE group, respectively (P < 0.05). In HepG2 cells, activation of GPR109A resulted in remarkable inhibition of oleic acid-induced lipid accumulation via a protein kinase C-extracellular signal-regulated kinase-1/2-AMP-activated protein kinase signaling pathway.
CONCLUSIONS
NA inhibits hepatic lipogenesis in C57BL/6 mice through a GPR109A-mediated signaling pathway, consistent with the mechanistic studies in HepG2 cells, suggesting its potential for treatment of NAFLD and other fatty liver diseases.