Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY, USA.
Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, PR China.
Int J Obes (Lond). 2017 Sep;41(9):1403-1412. doi: 10.1038/ijo.2017.128. Epub 2017 May 31.
Background &aims:Low levels of adiponectin (APN), an adipose-derived adipokine, are associated with obesity and non-alcoholic steatohepatitis although its role in high-fat diet-induced hepatic injury and steatosis remains unclear. Here we hypothesized that APN deficiency alters fat diet-induced hepatic function. To this end, we examined the effect of APN deficiency on high-fat diet-induced hepatic injury, apoptosis and steatosis.
Adult wild type and APN knockout mice were fed a low- or high-fat diet for 20 weeks. Serum levels of liver enzymes aspartate aminotransferase (AST), alanine aminotransferase (ALT), cholesterol, hepatic triglycerides, steatosis, pro-inflammatory cytokines, apoptosis and autophagy were examined.
High-fat feeding led to elevated body (48.2%) and liver weights (18.8%), increased levels of ALT (87.8%), serum cholesterol (104.4%), hepatic triglycerides (305.6%) and hepatic fat deposition as evidenced by Oil Red O staining, along with a reduced AST/ALT ratio and unchanged AST. Although APN knockout itself did not affect hepatic function and morphology, it reconciled fat diet-induced hepatic injury (P<0.05 vs WT-HF group) without reversing changes in body and liver weights, serum cholesterol and hepatic steatosis. In addition, fat diet intake promoted AMPK phosphorylation, p62 accumulation and apoptosis, including elevated Bax and cleaved Caspase-3 and downregulated Bcl-2, along with suppressed phosphorylation of Akt, STAT3 and JNK, and the autophagy makers Atg7, Beclin-1 and LC3B (P<0.05 vs WT-LF group) without affecting hepatic interlelukin-6 and tumor necrosis factor-α levels, the effects were reversed or significantly attenuated by APN knockout (P<0.05 vs WT-HF group). In vitro study using HepG2 cells revealed that STAT3 activation rescued palmitic acid-induced cell injury whereas STAT3 inhibition nullified APN knockdown-offered beneficial effects.
Our results revealed that high-fat diet intake promotes hepatic steatosis, apoptosis and interrupted autophagy. APN knockout elicits protective effect against hepatic injury possibly associated with autophagy regulation despite persistent hepatic steatosis.
背景与目的：脂肪细胞因子脂联素（APN）水平低与肥胖和非酒精性脂肪性肝炎有关，尽管其在高脂肪饮食诱导的肝损伤和脂肪变性中的作用尚不清楚。在这里，我们假设 APN 缺乏会改变高脂肪饮食引起的肝功能。为此，我们研究了 APN 缺乏对高脂肪饮食诱导的肝损伤、细胞凋亡和脂肪变性的影响。
成年野生型和 APN 敲除小鼠分别用低脂肪或高脂肪饮食喂养 20 周。检测血清肝酶天冬氨酸氨基转移酶（AST）、丙氨酸氨基转移酶（ALT）、胆固醇、肝甘油三酯、脂肪变性、促炎细胞因子、细胞凋亡和自噬的水平。
高脂肪喂养导致体重（48.2%）和肝脏重量（18.8%）增加，ALT（87.8%）、血清胆固醇（104.4%）、肝甘油三酯（305.6%）和油红 O 染色显示的肝脂肪沉积增加，AST/ALT 比值降低，AST 不变。尽管 APN 敲除本身并不影响肝功能和形态，但它缓解了高脂肪饮食诱导的肝损伤（与 WT-HF 组相比，P<0.05），而体重和肝脏重量、血清胆固醇和肝脂肪变性没有改变。此外，高脂肪饮食摄入促进了 AMPK 磷酸化、p62 积累和细胞凋亡，包括 Bax 和 cleaved Caspase-3 的增加以及 Bcl-2 的减少，同时还抑制了 Akt、STAT3 和 JNK 的磷酸化以及自噬标志物 Atg7、Beclin-1 和 LC3B（与 WT-LF 组相比，P<0.05），而不影响肝白细胞介素-6 和肿瘤坏死因子-α水平，APN 敲除则逆转或显著减轻了这些影响（与 WT-HF 组相比，P<0.05）。体外研究使用 HepG2 细胞表明，STAT3 激活挽救了棕榈酸诱导的细胞损伤，而 STAT3 抑制则消除了 APN 敲低带来的有益作用。
我们的研究结果表明，高脂肪饮食摄入可促进肝脂肪变性、细胞凋亡和自噬中断。APN 敲除对肝损伤具有保护作用，尽管肝脂肪变性持续存在，但可能与自噬调节有关。
