Department of Internal Medicine, Section on Molecular Medicine, Wake Forest University School of Medicine, Winston Salem, NC, USA.
Wake Forest Baptist Comprehensive Cancer Center Proteomics and Metabolomics Shared Resource, Wake Forest University School of Medicine, Winston Salem, NC, USA.
J Lipid Res. 2023 Aug;64(8):100405. doi: 10.1016/j.jlr.2023.100405. Epub 2023 Jun 22.
Alpha/beta hydrolase domain-containing protein 4 (ABHD4) catalyzes the deacylation of N-acyl phosphatidyl-ethanolamine (NAPE) and lyso-NAPE to produce glycerophospho-N-acyl ethanolamine (GP-NAE). Through a variety of metabolic enzymes, NAPE, lyso-NAPE, and GP-NAE are ultimately converted into NAE, a group of bioactive lipids that control many physiological processes including inflammation, cognition, food intake, and lipolysis (i.e., oleoylethanolamide or OEA). In a diet-induced obese mouse model, adipose tissue Abhd4 gene expression positively correlated with adiposity. However, it is unknown whether Abhd4 is a causal or a reactive gene to obesity. To fill this knowledge gap, we generated an Abhd4 knockout (KO) 3T3-L1 pre-adipocyte. During adipogenic stimulation, Abhd4 KO pre-adipocytes had increased adipogenesis and lipid accumulation, suggesting Abhd4 is responding to (a reactive gene), not contributing to (not a causal gene), adiposity, and may serve as a mechanism for protecting against obesity. However, we did not observe any differences in adiposity and metabolic outcomes between whole-body Abhd4 KO or adipocyte-specific Abhd4 KO mice and their littermate control mice (both male and female) on chow or a high-fat diet. This might be because we found that deletion of Abhd4 did not affect NAE such as OEA production, even though Abhd4 was highly expressed in adipose tissue and correlated with fasting adipose OEA levels and lipolysis. These data suggest that ABHD4 regulates adipocyte differentiation in vitro but does not affect adipose tissue lipid metabolism in mice despite nutrient overload, possibly due to compensation from other NAPE and NAE metabolic enzymes.
α/β水解酶结构域蛋白 4（ABHD4）催化 N-酰基磷脂酰乙醇胺（NAPE）和溶血磷脂酰乙醇胺（lyso-NAPE）的去酰化作用，生成甘油磷酸酰基乙醇胺（GP-NAE）。通过各种代谢酶，NAPE、lyso-NAPE 和 GP-NAE 最终转化为 NAE，这是一组控制许多生理过程的生物活性脂质，包括炎症、认知、食物摄入和脂肪分解（即油酰乙醇胺或 OEA）。在饮食诱导的肥胖小鼠模型中，脂肪组织 Abhd4 基因表达与肥胖呈正相关。然而，尚不清楚 Abhd4 是肥胖的因果基因还是反应基因。为了填补这一知识空白，我们生成了 Abhd4 敲除（KO）3T3-L1 前脂肪细胞。在脂肪生成刺激期间，Abhd4 KO 前脂肪细胞的脂肪生成和脂质积累增加，表明 Abhd4 是对（反应基因）而不是肥胖（非因果基因）做出反应，并且可能作为一种预防肥胖的机制。然而，我们没有观察到全身 Abhd4 KO 或脂肪细胞特异性 Abhd4 KO 小鼠与其同窝对照小鼠（雄性和雌性）在正常饮食或高脂肪饮食下肥胖和代谢结果的任何差异。这可能是因为我们发现即使 Abhd4 在脂肪组织中高度表达并与空腹脂肪 OEA 水平和脂肪分解相关，但其缺失也不会影响 NAE（如 OEA）的产生。这些数据表明 ABHD4 在体外调节脂肪细胞分化，但尽管存在营养过载，它并不影响小鼠脂肪组织的脂质代谢，这可能是由于其他 NAPE 和 NAE 代谢酶的代偿作用。
