Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Beth Israel Deaconess Medical Center (BIDMC) and Harvard Medical School, Boston, MA 02215, USA.
Labcorp, Morrisville, NC 27560, USA.
Int J Mol Sci. 2023 Aug 28;24(17):13332. doi: 10.3390/ijms241713332.
Nonalcoholic fatty liver disease (NAFLD) is associated with mitochondrial damage. Circulating mitochondrial metabolites may be elevated in NAFLD but their associations with liver damage is not known. This study aimed to assess the association of key mitochondrial metabolites with the degree of liver fibrosis in the context of NAFLD and nonalcoholic steatohepatitis (NASH). Cross-sectional analyses were performed on two cohorts of biopsy-proven NAFLD and/or NASH subjects. The association of circulating mitochondrial metabolite concentrations with liver fibrosis was assessed using linear regression analysis. In the single-center cohort of NAFLD subjects (n = 187), the mean age was 54.9 ±13.0 years, 40.1% were female and 86.1% were White. Type 2 diabetes (51.3%), hypertension (43.9%) and obesity (72.2%) were prevalent. Those with high citrate had a higher proportion of moderate/significant liver fibrosis (stage F ≥ 2) (68.4 vs. 39.6%, = 0.001) and advanced fibrosis (stage F ≥ 3) (31.6 vs. 13.6%, = 0.01). Citrate was associated with liver fibrosis independent of age, sex, NAFLD activity score and metabolic syndrome (per 1 SD increase: β = 0.19, 95% CI: 0.03-0.35, = 0.02). This association was also observed in a cohort of NASH subjects (n = 176) (β = 0.21, 95% CI: 0.07-0.36, = 0.005). The association of citrate with liver fibrosis was observed in males ( = 0.005) but not females ( = 0.41). In conclusion, circulating citrate is elevated and associated with liver fibrosis, particularly in male subjects with NAFLD and NASH. Mitochondrial function may be a target to consider for reducing the progression of liver fibrosis and NASH.
非酒精性脂肪性肝病 (NAFLD) 与线粒体损伤有关。循环线粒体代谢物在 NAFLD 中可能升高，但它们与肝损伤的关系尚不清楚。本研究旨在评估在 NAFLD 和非酒精性脂肪性肝炎 (NASH) 背景下，关键线粒体代谢物与肝纤维化程度的相关性。对两个经活检证实的 NAFLD 和/或 NASH 受试者队列进行了横断面分析。使用线性回归分析评估循环线粒体代谢物浓度与肝纤维化的相关性。在单中心 NAFLD 受试者队列 (n = 187) 中，平均年龄为 54.9 ± 13.0 岁，40.1%为女性，86.1%为白人。2 型糖尿病 (51.3%)、高血压 (43.9%) 和肥胖症 (72.2%) 较为普遍。柠檬酸水平较高者中肝纤维化程度为中度/显著 (F 分期≥2) 的比例较高 (68.4%比 39.6%， = 0.001) 和晚期纤维化 (F 分期≥3) (31.6%比 13.6%， = 0.01)。柠檬酸与肝纤维化的相关性独立于年龄、性别、NAFLD 活动评分和代谢综合征 (每增加 1 个标准差：β = 0.19，95%CI：0.03-0.35， = 0.02)。在 NASH 受试者队列 (n = 176) 中也观察到了这种相关性 (β = 0.21，95%CI：0.07-0.36， = 0.005)。柠檬酸与肝纤维化的相关性仅在男性中观察到 ( = 0.005)，而在女性中未观察到 ( = 0.41)。总之，循环柠檬酸水平升高与肝纤维化相关，尤其是在男性 NAFLD 和 NASH 患者中。线粒体功能可能是降低肝纤维化和 NASH 进展的一个治疗靶点。
