Acyl CoA synthetase 5 (ACSL5) ablation in mice increases energy expenditure and insulin sensitivity and delays fat absorption.
Acyl CoA synthetase 5 (ACSL5) ablation in mice increases energy expenditure and insulin sensitivity and delays fat absorption.
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DOI：
10.1016/j.molmet.2016.01.001
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发表时间：
2016-03
影响因子：
8.1
通讯作者：
Greenberg AS
中科院分区：
文献类型：
--
作者：
Bowman TA;O'Keeffe KR;D'Aquila T;Yan QW;Griffin JD;Killion EA;Salter DM;Mashek DG;Buhman KK;Greenberg AS
酰基辅酶a合成酶家族（ACSL）激活细胞内脂肪酸生成长链脂肪酸酰基辅酶a （FACoA）。facoa的不同代谢命运，如纳入中性脂质、磷脂和氧化途径，受到ACSL亚型的不同调节。体外研究表明ACSL5在甘油三酯合成中起作用；然而，我们对这种ACSL异构体在体内的作用了解有限。为了阐明ACSL5在体内的作用，我们生成了一种所有组织中都不表达ACSL5的小鼠（ACSL5−/−）。消融ACSL5可使空肠黏膜中ACSL活性降低~ 80%，肝脏中降低~ 50%，棕色脂肪组织裂解物中降低~ 37%。体成分研究表明，与对照组ACSL5loxP/loxP相比，ACSL5−/−小鼠的脂肪量和脂肪垫重量显著减少。间接量热研究表明，ACSL5 - / -增加了代谢率，并且在暗期增加了呼吸商。在ACSL5−/−小鼠中，空腹血糖和血清甘油三酯降低；在胰岛素耐量试验中，胰岛素敏感性得到改善。与ACSL5loxP/loxP相比，ACSL5−/−的肝脏mRNA（~ 16倍）和血清成纤维细胞生长因子21 （FGF21）水平（~ 13倍）均升高。与FGF21血清水平升高一致，解偶联蛋白-1基因（Ucp1）和ppar - γ辅助激活因子1- α基因（Pgc1α）转录水平在性腺脂肪组织中升高。为了进一步评价ACSL5在肠道中的功能，小鼠灌胃橄榄油丸；与对照小鼠相比，ACSL5 - / -小鼠血清中甘油三酯出现的速度被发现延迟。总之，ACSL5 - / -小鼠肝脏和血清FGF21水平升高，脂肪减少，胰岛素敏感性改善，能量消耗增加，甘油三酯吸收延迟。这些研究表明，ACSL5是全身能量代谢的重要调节因子，消融ACSL5可能对抗肥胖和胰岛素抵抗的发展。在ACSL5缺陷小鼠中研究了酰基辅酶a合成酶5 （ACSL5）在全身代谢中的作用。ACSL5缺乏降低了肝脏、肠道和棕色脂肪组织中ACSL的总活性。ACSL5缺陷小鼠肝脏和循环FGF21表达增加，能量消耗增加。ACSL5缺陷小鼠表现出甘油三酯吸收延迟。
The family of acyl-CoA synthetase enzymes (ACSL) activates fatty acids within cells to generate long chain fatty acyl CoA (FACoA). The differing metabolic fates of FACoAs such as incorporation into neutral lipids, phospholipids, and oxidation pathways are differentially regulated by the ACSL isoforms. In vitro studies have suggested a role for ACSL5 in triglyceride synthesis; however, we have limited understanding of the in vivo actions of this ACSL isoform. To elucidate the in vivo actions of ACSL5 we generated a line of mice in which ACSL5 expression was ablated in all tissues (ACSL5−/−). Ablation of ACSL5 reduced ACSL activity by ∼80% in jejunal mucosa, ∼50% in liver, and ∼37% in brown adipose tissue lysates. Body composition studies revealed that ACSL5−/−, as compared to control ACSL5loxP/loxP, mice had significantly reduced fat mass and adipose fat pad weights. Indirect calorimetry studies demonstrated that ACSL5−/− had increased metabolic rates, and in the dark phase, increased respiratory quotient. In ACSL5−/− mice, fasting glucose and serum triglyceride were reduced; and insulin sensitivity was improved during an insulin tolerance test. Both hepatic mRNA (∼16-fold) and serum levels of fibroblast growth factor 21 (FGF21) (∼13-fold) were increased in ACSL5−/− as compared to ACSL5loxP/loxP. Consistent with increased FGF21 serum levels, uncoupling protein-1 gene (Ucp1) and PPAR-gamma coactivator 1-alpha gene (Pgc1α) transcript levels were increased in gonadal adipose tissue. To further evaluate ACSL5 function in intestine, mice were gavaged with an olive oil bolus; and the rate of triglyceride appearance in serum was found to be delayed in ACSL5−/− mice as compared to control mice. In summary, ACSL5−/− mice have increased hepatic and serum FGF21 levels, reduced adiposity, improved insulin sensitivity, increased energy expenditure and delayed triglyceride absorption. These studies suggest that ACSL5 is an important regulator of whole-body energy metabolism and ablation of ACSL5 may antagonize the development of obesity and insulin resistance. Role of acyl CoA synthetase 5 (ACSL5) in systemic metabolism was studied in an ACSL5 deficient mouse. ACSL5 deficiency reduced total ACSL activity in liver, intestine, and brown adipose tissue. ACSL5 deficient mice had increased hepatic and circulating FGF21 expression and energy expenditure. ACSL5 deficient mice demonstrated delayed triglyceride absorption.