NAFLD is closely linked with hepatic insulin resistance. Accumulation of hepatic diacylglycerol activates PKC-ε, impairing insulin receptor activation and insulin-stimulated glycogen synthesis. Peripheral insulin resistance indirectly influences hepatic glucose and lipid metabolism by increasing flux of substrates that promote lipogenesis (glucose and fatty acids) and gluconeogenesis (glycerol and fatty acid-derived acetyl-CoA, an allosteric activator of pyruvate carboxylase). Weight loss with diet or bariatric surgery effectively treats NAFLD, but drugs specifically approved for NAFLD are not available. Some new pharmacological strategies act broadly to alter energy balance or influence pathways that contribute to NAFLD (e.g., agonists for PPAR γ, PPAR α/δ, FXR and analogs for FGF-21, and GLP-1). Others specifically inhibit key enzymes involved in lipid synthesis (e.g., mitochondrial pyruvate carrier, acetyl-CoA carboxylase, stearoyl-CoA desaturase, and monoacyl- and diacyl-glycerol transferases). Finally, a novel class of liver-targeted mitochondrial uncoupling agents increases hepatocellular energy expenditure, reversing the metabolic and hepatic complications of NAFLD.

中文翻译：

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非酒精性脂肪性肝病作为代谢性和肝病的纽带

NAFLD与肝胰岛素抵抗密切相关。肝二酰基甘油的积累会激活PKC-ε，损害胰岛素受体的激活和胰岛素刺激的糖原合成。外周胰岛素抵抗通过增加底物通量来间接影响肝葡萄糖和脂质代谢，底物通量促进脂肪生成（葡萄糖和脂肪酸）和葡萄糖异生（甘油和脂肪酸衍生的乙酰辅酶A，丙酮酸羧化酶的变构活化剂）。通过饮食或减肥手术减肥可以有效治疗NAFLD，但尚无专门批准用于NAFLD的药物。一些新的药理策略广泛起作用，以改变能量平衡或影响有助于NAFLD的途径（例如，PPARγ，PPARα/δ，FXR激动剂和FGF-21和GLP-1的类似物）。其他一些特异性抑制参与脂质合成的关键酶（例如线粒体丙酮酸载体，乙酰辅酶A羧化酶，硬脂酰辅酶A去饱和酶以及单酰基和二酰基甘油转移酶）。最后，一类新型的肝靶向线粒体解偶联剂增加了肝细胞的能量消耗，从而逆转了NAFLD的代谢和肝脏并发症。