Division of Gastroenterology, Ospedale di Acireale, Azienda Sanitaria Provinciale di Catania, Catania, Italy.
Department PROMISE, University of Palermo, Palermo, Italy.
J Hepatol. 2024 Jan;80(1):10-19. doi: 10.1016/j.jhep.2023.09.020. Epub 2023 Oct 25.
BACKGROUND & AIMS: Sirtuin 5, encoded by the SIRT5 gene, is a NAD-dependent deacylase that modulates mitochondrial metabolic processes through post-translational modifications. In this study, we aimed to examine the impact of the SIRT5 rs12216101 T>G non-coding single nucleotide polymorphism on disease severity in patients with non-alcoholic fatty liver disease (NAFLD).
The rs12216101 variant was genotyped in 2,606 consecutive European patients with biopsy-proven NAFLD. Transcriptomic analysis, expression of mitochondrial complexes and oxidative stress levels were measured in liver samples from a subset of bariatric patients. Effects of SIRT5 pharmacological inhibition were evaluated in HepG2 cells exposed to excess free fatty acids. Mitochondrial energetics in vitro were investigated by high-performance liquid chromatography.
In the whole cohort, the frequency distribution of SIRT5 rs12216101 TT, TG and GG genotypes was 47.0%, 42.3% and 10.7%, respectively. At multivariate logistic regression analysis adjusted for sex, age >50 years, diabetes, and PNPLA3 rs738409 status, the SIRT5 rs12216101 T>G variant was associated with the presence of non-alcoholic steatohepatitis (odds ratio 1.20, 95% CI 1.03-1.40) and F2-F4 fibrosis (odds ratio 1.18; 95% CI 1.00-1.37). Transcriptomic analysis showed that the SIRT5 rs12216101 T>G variant was associated with upregulation of transcripts involved in mitochondrial metabolic pathways, including the oxidative phosphorylation system. In patients carrying the G allele, western blot analysis confirmed an upregulation of oxidative phosphorylation complexes III, IV, V and consistently higher levels of reactive oxygen species, reactive nitrogen species and malondialdehyde, and lower ATP levels. Administration of a pharmacological SIRT5 inhibitor preserved mitochondrial energetic homeostasis in HepG2 cells, as evidenced by restored ATP/ADP, NAD+/NADH, NADP+/NADPH ratios and glutathione levels.
The SIRT5 rs12216101 T>G variant, heightening SIRT5 activity, is associated with liver damage, mitochondrial dysfunction, and oxidative stress in patients with NAFLD.
In this study we discovered that the SIRT5 rs12216101 T>G variant is associated with higher disease severity in patients with non-alcoholic fatty liver disease (NAFLD). This risk variant leads to a SIRT5 gain-of-function, enhancing mitochondrial oxidative phosphorylation and thus leading to oxidative stress. SIRT5 may represent a novel disease modulator in NAFLD.
编码酶 Sirtuin 5 的 SIRT5 基因是一种 NAD 依赖性去乙酰化酶，通过翻译后修饰调节线粒体代谢过程。本研究旨在探讨 SIRT5 rs12216101T>G 非编码单核苷酸多态性对非酒精性脂肪性肝病 (NAFLD) 患者疾病严重程度的影响。
对 2606 例经活检证实的 NAFLD 连续欧洲患者进行 rs12216101 变异基因分型。在一组减肥患者的肝组织样本中进行转录组分析、线粒体复合物表达和氧化应激水平的测量。在暴露于过量游离脂肪酸的 HepG2 细胞中评估 SIRT5 药理学抑制的作用。通过高效液相色谱法研究体外线粒体能量代谢。
在整个队列中，SIRT5 rs12216101 TT、TG 和 GG 基因型的频率分布分别为 47.0%、42.3%和 10.7%。在调整性别、年龄>50 岁、糖尿病和 PNPLA3 rs738409 状态的多变量逻辑回归分析中，SIRT5 rs12216101T>G 变异与非酒精性脂肪性肝炎 (比值比 1.20，95%CI 1.03-1.40) 和 F2-F4 纤维化 (比值比 1.18；95%CI 1.00-1.37) 有关。转录组分析表明，SIRT5 rs12216101T>G 变异与参与线粒体代谢途径的转录本上调有关，包括氧化磷酸化系统。在携带 G 等位基因的患者中，Western blot 分析证实氧化磷酸化复合物 III、IV、V 的上调以及持续较高的活性氧、活性氮和丙二醛水平，以及较低的 ATP 水平。使用药理学 SIRT5 抑制剂可维持 HepG2 细胞中线粒体能量稳态，这表现为恢复的 ATP/ADP、NAD+/NADH、NADP+/NADPH 比值和谷胱甘肽水平。
SIRT5 rs12216101T>G 变异体增加 SIRT5 活性，与 NAFLD 患者的肝损伤、线粒体功能障碍和氧化应激有关。
本研究发现，SIRT5 rs12216101T>G 变异与非酒精性脂肪性肝病 (NAFLD) 患者的疾病严重程度较高有关。这种风险变异导致 SIRT5 获得功能，增强线粒体氧化磷酸化，从而导致氧化应激。SIRT5 可能是 NAFLD 的一种新型疾病调节剂。
