The I148M PNPLA3 polymorphism influences serum adiponectin in patients with fatty liver and healthy controls.
The I148M PNPLA3 polymorphism influences serum adiponectin in patients with fatty liver and healthy controls.
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DOI：
10.1186/1471-230x-12-111
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发表时间：
2012-08-16
影响因子：
2.4
通讯作者：
Fargion S
中科院分区：
文献类型：
--
作者：
Valenti L;Rametta R;Ruscica M;Dongiovanni P;Steffani L;Motta BM;Canavesi E;Fracanzani AL;Mozzi E;Roviaro G;Magni P;Fargion S
脂联素减少与非酒精性脂肪性肝病（NAFLD）和脂肪性肝炎（NASH）的发病机制有关，I148 M Patatin样磷脂酶结构域3（PNPLA 3）多态性通过尚未确定的机制（可能涉及脂肪组织功能的调节）易患NAFLD和NASH和慢性丙型肝炎（CHC）的肝损伤进展。本研究的目的是评估I148 M PNPLA 3多态性是否影响肝脏疾病和健康对照者的血清脂联素。为此，我们考虑了144例连续的意大利NAFLD患者，261例CHC患者，35例严重肥胖受试者和257例脂肪变性概率极低的健康对照者，所有患者均具有完整的临床和遗传特征，包括脂联素（ADIPOQ）基因型。采用Taqman方法检测PNPLA 3 rs738409（I148 M）和ADIPOQ基因型，ELISA法检测血清脂联素水平。采用实时荧光定量PCR技术检测了35例接受减肥手术的肥胖受试者内脏脂肪组织（VAT）中脂联素mRNA水平。脂联素水平与NAFLD的风险和疾病的组织学严重程度独立相关。在NAFLD患者（p = 0.03）和健康受试者（p = 0.04）中，脂联素水平随着处于NASH风险的148个M PNPLA 3等位基因的数量而降低。在多变量分析中，PNPLA 3 148 M等位基因与低脂联素水平（<6 mg/ml，中位数）相关，与NAFLD诊断、年龄、性别、BMI和ADIPOQ基因型无关（OR 1.67，95% c.i. 1.07-2.1）。即使在没有NASH的情况下，p.148 M PNPLA 3变体也与肥胖患者VAT中脂联素mRNA水平降低相关（p < 0.05）。相反，在以脂联素抵抗为特征的CHC中，低脂联素与男性性别和脂肪变性相关，但与PNPLA 3和ADIPOQ基因型和病毒特征无关。I148 M PNPLA 3变异体与NAFLD患者和健康受试者的脂联素水平相关，但在CHC患者中不存在脂联素抵抗。I148 M PNPLA 3基因型可能代表血清脂联素水平的遗传决定因素。血清脂联素的调节可能参与介导不含CHC的148 M PNPLA 3变体携带者对脂肪变性、NASH和肝细胞癌的易感性，具有潜在的治疗意义。
Reduced adiponectin is implicated in the pathogenesis of nonalcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH), and the I148M Patatin-like phospholipase domain-containing 3 (PNPLA3) polymorphism predisposes to NAFLD and liver damage progression in NASH and chronic hepatitis C (CHC) by still undefined mechanisms, possibly involving regulation of adipose tissue function. Aim of this study was to evaluate whether the I148M PNPLA3 polymorphism influences serum adiponectin in liver diseases and healthy controls. To this end, we considered 144 consecutive Italian patients with NAFLD, 261 with CHC, 35 severely obese subjects, and 257 healthy controls with very low probability of steatosis, all with complete clinical and genetic characterization, including adiponectin (ADIPOQ) genotype. PNPLA3 rs738409 (I148M) and ADIPOQ genotypes were evaluated by Taqman assays, serum adiponectin by ELISA. Adiponectin mRNA levels were evaluated by quantitative real-time PCR in the visceral adipose tissue (VAT) of 35 obese subjects undergoing bariatric surgery. Adiponectin levels were independently associated with the risk of NAFLD and with the histological severity of the disease. Adiponectin levels decreased with the number of 148 M PNPLA3 alleles at risk of NASH both in patients with NAFLD (p = 0.03), and in healthy subjects (p = 0.04). At multivariate analysis, PNPLA3 148 M alleles were associated with low adiponectin levels (<6 mg/ml, median value) independently of NAFLD diagnosis, age, gender, BMI, and ADIPOQ genotype (OR 1.67, 95% c.i. 1.07-2.1 for each 148 M allele). The p.148 M PNPLA3 variant was associated with decreased adiponectin mRNA levels in the VAT of obese patients (p < 0.05) even in the absence of NASH. In contrast, in CHC, characterized by adiponectin resistance, low adiponectin was associated with male gender and steatosis, but not with PNPLA3 and ADIPOQ genotypes and viral features. The I148M PNPLA3 variant is associated with adiponectin levels in patients with NAFLD and in healthy subjects, but in the presence of adiponectin resistance not in CHC patients. The I148M PNPLA3 genotype may represent a genetic determinant of serum adiponectin levels. Modulation of serum adiponectin might be involved in mediating the susceptibility to steatosis, NASH, and hepatocellular carcinoma in carriers of the 148 M PNPLA3 variant without CHC, with potential therapeutic implications.