Institut National de la Santé et de la Recherche Médicale, U895, Team 8, Hepatic Complications in Obesity, Nice F-06204, Cedex 3, France.
Clin Res Hepatol Gastroenterol. 2011 Jun;35 Suppl 1:S10-20. doi: 10.1016/S2210-7401(11)70003-1.
Mechanisms of liver fibrosis are complex and varied. Among them, metabolic factors are particularly important in the development of fibrosis associated with nonalcoholic steatohepatitis (NASH). These factors are some of the "multiple parallel hits" responsible for liver damage during NASH. Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome. Major profibrogenic protagonists, such as hepatic stellate cells and Kupffer cells, are activated by insulin resistance, apoptosis and local inflammation. Relations between steatosis, insulin resistance and fibrosis are complex. Initially, simple steatosis may be a way to store deleterious free fatty acid in neutral triglycerides. If the lipid storage threshold is exceeded, steatosis may become associated with lipotoxicity. Similarly, interindividual variations of adipose tissue expandability might explain various phenotypes, ranging from "metabolically obese patients with normal weight" to "metabolically normal morbidly obese patients". The metabolic abnormalities in subcutaneous and visceral adipose tissue are insulin resistance and low-grade inflammation, which are associated with increased release of free fatty acid flux and changes in adipocytokines production such as leptin, adiponectin and interleukin 6. The nuclear transcription factor peroxisome proliferator-activated receptor gamma (PPARγ) and the endocannabinoid system might have important roles in liver fibrogenesis and are potential therapeutic targets. Finally, with the development of new molecular tools, gut microbiota has been recently identified for its pleiotropic functions, including metabolism regulation. Better knowledge of these mechanisms should lead to new strategies for the treatment of metabolic factors that play a key role in liver injuries.
肝纤维化的机制复杂多样。其中，代谢因素在非酒精性脂肪性肝炎（NASH）相关纤维化的发展中尤为重要。这些因素是导致 NASH 期间肝损伤的“多个平行打击”的一部分。非酒精性脂肪性肝病（NAFLD）是代谢综合征的肝脏表现。主要的致纤维化主角，如肝星状细胞和枯否细胞，通过胰岛素抵抗、细胞凋亡和局部炎症而被激活。脂肪变性、胰岛素抵抗和纤维化之间的关系很复杂。最初，单纯性脂肪变性可能是一种将有害游离脂肪酸储存在中性甘油三酯中的方式。如果脂质储存阈值超过，脂肪变性可能会与脂毒性相关联。同样，脂肪组织扩展性的个体间差异可能解释了各种表型，从“代谢肥胖但体重正常的患者”到“代谢正常但病态肥胖的患者”。皮下和内脏脂肪组织的代谢异常是胰岛素抵抗和低度炎症，这与游离脂肪酸通量的释放增加以及瘦素、脂联素和白细胞介素 6 等脂肪细胞因子的产生变化有关。核转录因子过氧化物酶体增殖物激活受体γ（PPARγ）和内源性大麻素系统可能在肝纤维化发生中具有重要作用，是潜在的治疗靶点。最后，随着新的分子工具的发展，肠道微生物群因其代谢调节等多种功能而最近被确定。更好地了解这些机制应该会为治疗在肝损伤中起关键作用的代谢因素提供新的策略。
