Jang Jung Eun, Park Han-Sol, Yoo Hyun Ju, Baek In-Jeoung, Yoon Ji Eun, Ko Myoung Seok, Kim Ah-Ram, Kim Hyoun Sik, Park Hye-Sun, Lee Seung Eun, Kim Seung-Whan, Kim Su Jung, Leem Jaechan, Kang Yu Mi, Jung Min Kyo, Pack Chan-Gi, Kim Chong Jai, Sung Chang Ohk, Lee In-Kyu, Park Joong-Yeol, Fernández-Checa José C, Koh Eun Hee, Lee Ki-Up
Department of Internal Medicine, University of Ulsan College of Medicine, Seoul, Republic of Korea.
Asan Institute for Life Sciences, University of Ulsan College of Medicine, Seoul, Republic of Korea.
Hepatology. 2017 Aug;66(2):416-431. doi: 10.1002/hep.29039. Epub 2017 Jun 29.
Free cholesterol (FC) accumulation in the liver is an important pathogenic mechanism of nonalcoholic steatohepatitis (NASH). Plasmalogens, key structural components of the cell membrane, act as endogenous antioxidants and are primarily synthesized in the liver. However, the role of hepatic plasmalogens in metabolic liver disease is unclear. In this study, we found that hepatic levels of docosahexaenoic acid (DHA)-containing plasmalogens, expression of glyceronephosphate O-acyltransferase (Gnpat; the rate-limiting enzyme in plasmalogen biosynthesis), and expression of Pparα were lower in mice with NASH caused by accumulation of FC in the liver. Cyclodextrin-induced depletion of FC transactivated Δ-6 desaturase by increasing sterol regulatory element-binding protein 2 expression in cultured hepatocytes. DHA, the major product of Δ-6 desaturase activation, activated GNPAT, thereby explaining the association between high hepatic FC and decreased Gnpat expression. Gnpat small interfering RNA treatment significantly decreased peroxisome proliferator-activated receptor α (Pparα) expression in cultured hepatocytes. In addition to GNPAT, DHA activated PPARα and increased expression of Pparα and its target genes, suggesting that DHA in the DHA-containing plasmalogens contributed to activation of PPARα. Accordingly, administration of the plasmalogen precursor, alkyl glycerol (AG), prevented hepatic steatosis and NASH through a PPARα-dependent increase in fatty acid oxidation. Gnpat mice were more susceptible to hepatic lipid accumulation and less responsive to the preventive effect of fluvastatin on NASH development, suggesting that endogenous plasmalogens prevent hepatic steatosis and NASH.
Increased hepatic FC in animals with NASH decreased plasmalogens, thereby sensitizing animals to hepatocyte injury and NASH. Our findings uncover a novel link between hepatic FC and plasmalogen homeostasis through GNPAT regulation. Further study of AG or other agents that increase hepatic plasmalogen levels may identify novel therapeutic strategies against NASH. (Hepatology 2017;66:416-431).
肝脏中游离胆固醇（FC）的积累是非酒精性脂肪性肝炎（NASH）的重要致病机制。缩醛磷脂作为细胞膜的关键结构成分，具有内源性抗氧化剂的作用，主要在肝脏中合成。然而，肝脏缩醛磷脂在代谢性肝病中的作用尚不清楚。在本研究中，我们发现，肝脏中因FC积累而导致NASH的小鼠，其肝脏中含二十二碳六烯酸（DHA）的缩醛磷脂水平、甘油磷酸O-酰基转移酶（Gnpat，缩醛磷脂生物合成中的限速酶）的表达以及过氧化物酶体增殖物激活受体α（Pparα）的表达均较低。环糊精诱导的FC耗竭通过增加培养肝细胞中固醇调节元件结合蛋白2的表达来反式激活Δ-6去饱和酶。DHA是Δ-6去饱和酶激活的主要产物，可激活GNPAT，从而解释了肝脏中高FC与Gnpat表达降低之间的关联。Gnpat小干扰RNA处理显著降低了培养肝细胞中过氧化物酶体增殖物激活受体α（Pparα）的表达。除了GNPAT外，DHA还激活PPARα并增加Pparα及其靶基因的表达，这表明含DHA的缩醛磷脂中的DHA有助于PPARα的激活。因此，给予缩醛磷脂前体烷基甘油（AG）可通过PPARα依赖性的脂肪酸氧化增加来预防肝脏脂肪变性和NASH。Gnpat基因敲除小鼠更容易发生肝脏脂质积累，并且对氟伐他汀对NASH发展的预防作用反应较小，这表明内源性缩醛磷脂可预防肝脏脂肪变性和NASH。
NASH动物肝脏中FC增加会降低缩醛磷脂水平，从而使动物对肝细胞损伤和NASH敏感。我们的研究结果揭示了通过GNPAT调节肝脏FC与缩醛磷脂稳态之间的新联系。对AG或其他可增加肝脏缩醛磷脂水平的药物的进一步研究可能会确定针对NASH的新治疗策略。（《肝脏病学》2017年；66：416 - 431）
