Department of Nutrition, Dietetics, and Food Science, Brigham Young University, Provo, UT 84602, USA.
Department of Physiology and Developmental Biology, Brigham Young University, Provo, UT 84602, USA.
Diabetol Metab Syndr. 2013 May 31;5:29. doi: 10.1186/1758-5996-5-29. eCollection 2013.
High fat feeding increases hepatic fat accumulation and is associated with hepatic insulin resistance. AMP Activated Protein Kinase (AMPK) is thought to inhibit lipid synthesis by the acute inhibition of glycerol-3-phosphate acyltransferase (GPAT) activity and transcriptional regulation via sterol regulatory element binding protein-1c (SREBP-1c).
The purpose of this study was to determine if chronic activation of AMPK prevented an increase in GPAT1 activity in rats fed a high fat diet. Rats were fed a control (C), or a high fat (HF) diet (60% fat) for 6 weeks and injected with saline or a daily aminoimidazole carboxamide ribnucleotide (AICAR) dose of 0.5 mg/g body weight.
Chronic AMPK activation by AICAR injections resulted in a significant reduction in hepatic triglyceride accumulation in both the C and HF fed animals (C, 5.5±0.7; C+AICAR, 2.7 ±0.3; HF, 21.8±3.3; and HF+AICAR, 8.0±1.8 mg/g liver). HF feeding caused an increase in total GPAT and GPAT1 activity, which was not affected by chronic AMPK activation (GPAT1 activity vs. C, C+AICAR, 92±19%; HF, 186±43%; HF+AICAR, 234±62%). Markers of oxidative capacity, including citrate synthase activity and cytochrome c abundance, were not affected by chronic AICAR treatment. Interestingly, HF feeding caused a significant increase in long chain acyl-CoA dehydrogenase or LCAD (up 66% from C), a marker of fatty acid oxidation capacity.
These results suggest that chronic AMPK activation limits hepatic triglyceride accumulation independent of a reduction in total GPAT1 activity.
高脂喂养会增加肝脂肪堆积，并与肝胰岛素抵抗有关。AMP 激活的蛋白激酶（AMPK）被认为通过甘油-3-磷酸酰基转移酶（GPAT）活性的急性抑制和固醇调节元件结合蛋白-1c（SREBP-1c）的转录调节来抑制脂质合成。
本研究旨在确定慢性 AMPK 激活是否能防止高脂喂养大鼠的 GPAT1 活性增加。大鼠分别喂食对照（C）或高脂（HF）饮食（60%脂肪）6 周，并注射生理盐水或每日氨基咪唑羧酰胺核苷酸（AICAR）剂量为 0.5mg/g 体重。
AICAR 注射慢性 AMPK 激活导致 C 和 HF 喂养动物的肝甘油三酯积累显著减少（C：5.5±0.7；C+AICAR：2.7±0.3；HF：21.8±3.3；HF+AICAR：8.0±1.8mg/g 肝）。HF 喂养导致总 GPAT 和 GPAT1 活性增加，而慢性 AMPK 激活对此没有影响（GPAT1 活性与 C、C+AICAR 相比：92±19%；HF：186±43%；HF+AICAR：234±62%）。氧化能力标志物，包括柠檬酸合酶活性和细胞色素 c 丰度，不受慢性 AICAR 治疗的影响。有趣的是，HF 喂养导致长链酰基辅酶 A 脱氢酶或 LCAD（比 C 增加 66%）显著增加，这是脂肪酸氧化能力的标志物。
这些结果表明，慢性 AMPK 激活可限制肝甘油三酯积累，而与总 GPAT1 活性降低无关。
