The PNPLA3-I148M variant increases polyunsaturated triglycerides in human adipose tissue
The PNPLA3-I148M variant increases polyunsaturated triglycerides in human adipose tissue
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DOI：
10.1111/liv.14507
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发表时间：
2020-05-18
影响因子：
6.7
通讯作者：
Yki-Jarvinen, Hannele
中科院分区：
文献类型：
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作者：
Qadri, Sami;Lallukka-Bruck, Susanna;Yki-Jarvinen, Hannele
背景与目的PNPLA 3中的I148 M变异是非酒精性脂肪性肝病（NAFLD）的主要遗传危险因素。肝脏富含PNPLA 3-I148 M载体中的多不饱和甘油三酯（PUFA-TG）。基因表达数据表明PNPLA 3在人类中是肝脏特异性的，但它是否在脂肪组织（AT）中起作用尚不清楚。方法在125名志愿者（PNPLA 3（148 MM/MI），n = 63; PNPLA 3（148 II），n = 62）中进行AT脂质体和空腹血清非酯化脂肪酸（NEFA）组成的分析。在50名志愿者中测定AT脂肪酸组成，所述志愿者对于所述变体（PNPLA 3（148 MM），n = 25）是纯合的或缺乏所述变体（PNPLA 3（148 II），n = 25）。用[H-2（5）]甘油测定脂肪分解的全身胰岛素敏感性，并测定部分志愿者皮下AT和肝活检组织中PNPLA 3 mRNA和蛋白水平。该变体并没有改变脂解率或空腹血清NEFA的组成。PNPLA 3 mRNA在肝脏中比AT高33倍（P <0.0001）。相比之下，每个组织蛋白的PNPLA 3蛋白水平在AT中比肝脏高3倍（P <0.0001），并且当与全身AT和肝脏组织质量相关时高9倍（P <0.0001）。PNPLA 3-I148 M局部重塑AT TG以变得多不饱和，就像它在肝脏中那样，而不影响脂解或血清NEFA的组成。AT代谢的变化不会导致PNPLA 3-I148 M携带者的NAFLD。
Background & Aims The I148M variant in PNPLA3 is the major genetic risk factor for non-alcoholic fatty liver disease (NAFLD). The liver is enriched with polyunsaturated triglycerides (PUFA-TGs) in PNPLA3-I148M carriers. Gene expression data indicate that PNPLA3 is liver-specific in humans, but whether it functions in adipose tissue (AT) is unknown. We investigated whether PNPLA3-I148M modifies AT metabolism in human NAFLD.Methods Profiling of the AT lipidome and fasting serum non-esterified fatty acid (NEFA) composition was conducted in 125 volunteers (PNPLA3(148MM/MI), n = 63; PNPLA3(148II), n = 62). AT fatty acid composition was determined in 50 volunteers homozygous for the variant (PNPLA3(148MM), n = 25) or lacking the variant (PNPLA3(148II), n = 25). Whole-body insulin sensitivity of lipolysis was determined using [H-2(5)]glycerol, and PNPLA3 mRNA and protein levels were measured in subcutaneous AT and liver biopsies in a subset of the volunteers.Results PUFA-TGs were significantly increased in AT in carriers versus non-carriers of PNPLA3-I148M. The variant did not alter the rate of lipolysis or the composition of fasting serum NEFAs. PNPLA3 mRNA was 33-fold higher in the liver than in AT (P < .0001). In contrast, PNPLA3 protein levels per tissue protein were three-fold higher in AT than the liver (P < .0001) and nine-fold higher when related to whole-body AT and liver tissue masses (P < .0001).Conclusions Contrary to previous assumptions, PNPLA3 is highly abundant in AT. PNPLA3-I148M locally remodels AT TGs to become polyunsaturated as it does in the liver, without affecting lipolysis or composition of serum NEFAs. Changes in AT metabolism do not contribute to NAFLD in PNPLA3-I148M carriers.