Hepatometabolic Unit, Bambino Gesù Children's Hospital, Rome, Italy; Department of Pediatrics and Infantile Neuropsychiatry, Sapienza University of Rome, Italy.
Department of Movement, Human and Health Sciences, University of Rome "Foro Italico", Rome, Italy.
J Pediatr. 2018 Mar;194:100-108.e3. doi: 10.1016/j.jpeds.2017.10.036. Epub 2017 Dec 1.
To investigate whether the modulation of local cellular cross-talks and the modification of hepatic adipocytokine expression could mechanistically explain the improvement of liver histopathology after laparoscopic sleeve gastrectomy (LSG) in adolescents with nonalcoholic fatty liver disease (NAFLD).
Twenty obese (body mass index of ≥35 kg/m) adolescents who underwent LSG and with biopsy-proven NAFLD were included. At baseline (T0) and 1 year after treatment, patients underwent clinical evaluation, blood tests, and liver biopsy. Hepatic progenitor cells, hepatic stellate cells (HSCs), macrophages, and adipocytokines were evaluated by immunohistochemistry and immunofluorescence.
Liver biopsy samples after LSG demonstrated a significant improvement of NAFLD Activity Score and fibrosis. Immunohistochemistry indicated a significant reduction of hepatocyte cell cycle arrest, ductular reaction, activated HSC, and macrophage number after LSG compared with T0. The activation state of HSC was accompanied by modification in the expression of the autophagy marker LC3. Hepatocyte expression of adiponectin was significant higher after LSG than into T0. Moreover, LSG caused decreased resistin expression in Sox9 hepatic progenitor cells compared with T0. The number of S100A9 macrophages was also reduced by LSG correlating with resistin expression. Finally, serum levels of proinflammatory cytokines significantly correlated with macrophages and activated HSC numbers.
The histologic improvement induced by LSG is associated with the reduced activation of local cellular compartments (hepatic progenitor cells, HSCs, and macrophages), thus, strengthening the role of cellular interactions and hepatic adipocytokine production in the pathogenesis of NAFLD.
研究局部细胞串扰的调节和肝脂肪细胞因子表达的修饰是否能从机制上解释腹腔镜袖状胃切除术（LSG）治疗青少年非酒精性脂肪性肝病（NAFLD）后肝组织病理学改善的原因。
20 名肥胖（体质量指数≥35kg/m）且经肝活检证实患有 NAFLD 的青少年接受了 LSG。在基线（T0）和治疗 1 年后，患者接受了临床评估、血液检查和肝活检。通过免疫组化和免疫荧光法评估肝祖细胞、肝星状细胞（HSCs）、巨噬细胞和脂肪细胞因子。
LSG 后的肝活检样本显示 NAFLD 活动评分和纤维化有显著改善。与 T0 相比，免疫组化显示 LSG 后肝细胞细胞周期停滞、胆管反应、活化的 HSC 和巨噬细胞数量显著减少。HSC 的活化状态伴随着自噬标志物 LC3 的表达修饰。LSG 后肝实质细胞的脂联素表达明显高于 T0。此外，LSG 导致 Sox9 肝祖细胞中的抵抗素表达较 T0 降低。LSG 还与抵抗素表达相关，减少了 S100A9 巨噬细胞的数量。最后，促炎细胞因子的血清水平与巨噬细胞和活化的 HSC 数量显著相关。
LSG 引起的组织学改善与局部细胞区室（肝祖细胞、HSCs 和巨噬细胞）的活化减少有关，从而增强了细胞相互作用和肝脂肪细胞因子产生在 NAFLD 发病机制中的作用。
