Choi Steve S, Diehl Anna Mae
Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA.
Curr Opin Lipidol. 2008 Jun;19(3):295-300. doi: 10.1097/MOL.0b013e3282ff5e55.
Nonalcoholic fatty liver disease is a spectrum of diseases ranging from simple steatosis to cirrhosis. The hallmark of nonalcoholic fatty liver disease is hepatocyte accumulation of triglycerides. We will review the role of triglyceride synthesis in nonalcoholic fatty liver disease progression and summarize recent findings about triglyceride synthesis inhibition and prevention of progressive disease.
Attempts to inhibit triglyceride synthesis in animal models have resulted in improvement in hepatic steatosis. Studies in animal models of nonalcoholic fatty liver disease demonstrate that inhibition of acyl-coenzyme A:diacylglycerol acyltransferase, the enzyme that catalyzes the final step in triglyceride synthesis, results in improvement in hepatic steatosis and insulin sensitivity. We recently confirmed that hepatic specific inhibition of acyl-coenzyme A:diacylglycerol acyltransferase with antisense oligonucleotides improves hepatic steatosis in obese, diabetic mice but, unexpectedly, exacerbated injury and fibrosis in that model of progressive nonalcoholic fatty liver disease. When hepatocyte triglyceride synthesis was inhibited, free fatty acids accumulated in the liver, leading to induction of fatty acid oxidizing systems that increased hepatic oxidative stress and liver damage. These findings suggest that the ability to synthesize triglycerides may, in fact, be protective in obesity.
Nonalcoholic fatty liver disease is strongly associated with obesity and peripheral insulin resistance. Peripheral insulin resistance increases lipolysis in adipose depots, promoting increased free fatty acid delivery to the liver. In states of energy excess, such as obesity, the latter normally triggers hepatic triglyceride synthesis. When hepatic triglyceride synthesis is unable to accommodate increased hepatocyte free fatty acid accumulation, however, lipotoxicity results. Thus, rather than being hepatotoxic, liver triglyceride accumulation is actually hepato-protective in obese, insulin-resistant individuals.
非酒精性脂肪性肝病是一系列从单纯性脂肪变性到肝硬化的疾病。非酒精性脂肪性肝病的标志是肝细胞内甘油三酯的蓄积。我们将综述甘油三酯合成在非酒精性脂肪性肝病进展中的作用，并总结关于甘油三酯合成抑制及预防疾病进展的最新研究发现。
在动物模型中抑制甘油三酯合成的尝试已使肝脂肪变性得到改善。对非酒精性脂肪性肝病动物模型的研究表明，抑制酰基辅酶A：二酰甘油酰基转移酶（催化甘油三酯合成最后一步的酶）可改善肝脂肪变性和胰岛素敏感性。我们最近证实，用反义寡核苷酸对酰基辅酶A：二酰甘油酰基转移酶进行肝脏特异性抑制可改善肥胖、糖尿病小鼠的肝脂肪变性，但出乎意料的是，在该进行性非酒精性脂肪性肝病模型中会加剧损伤和纤维化。当肝细胞甘油三酯合成受到抑制时，游离脂肪酸在肝脏中蓄积，导致脂肪酸氧化系统的诱导，从而增加肝脏氧化应激和肝损伤。这些发现表明，实际上甘油三酯合成能力在肥胖状态下可能具有保护作用。
非酒精性脂肪性肝病与肥胖和外周胰岛素抵抗密切相关。外周胰岛素抵抗增加脂肪库中的脂肪分解，促进游离脂肪酸向肝脏的输送增加。在能量过剩状态下，如肥胖，后者通常会触发肝脏甘油三酯合成。然而，当肝脏甘油三酯合成无法适应肝细胞游离脂肪酸蓄积增加时，就会导致脂毒性。因此，对于肥胖、胰岛素抵抗个体，肝脏甘油三酯蓄积实际上具有肝脏保护作用，而非肝毒性。
