Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan; Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa-shi, Saitama 359-8513, Japan.
J Hepatol. 2017 Oct;67(4):780-790. doi: 10.1016/j.jhep.2017.05.020. Epub 2017 May 26.
BACKGROUND & AIMS: Although obesity is a risk factor for acute liver failure, the pathogenic mechanisms are not yet fully understood. High cholesterol (HC) intake, which often underlies obesity, is suggested to play a role in the mechanism. We aimed to elucidate the effect of a HC diet on acetaminophen-induced acute liver injury, the most frequent cause of acute liver failure in the USA.
C57BL/6 Toll-like receptor 9 (TLR9) knockout (Tlr9) mice and their Tlr9 littermates were fed an HC diet for fourweeks and then treated with acetaminophen. Liver sinusoidal endothelial cells (LSECs) were isolated from the mice for in vivo and in vitro analyses.
The HC diet exacerbated acetaminophen-induced acute liver injury in a TLR9/inflammasome pathway-dependent manner. LSECs played a major role in the cholesterol loading-induced exacerbation. The accumulation of free cholesterol in the endolysosomes in LSECs enhanced TLR9-mediated signaling, thereby exacerbating the pathology of acetaminophen-induced liver injury through the activation of the TLR9/inflammasome pathway. The accumulation of free cholesterol in LSEC endolysosomes induced a dysfunction of the Rab7 membrane trafficking recycling mechanism, thus disrupting the transport of TLR9 from late endosomes to the lysosomes. Consequently, the level of active TLR9 in the late endosomes increased, thereby enhancing TLR9 signaling in LSECs.
HC intake exaggerated acetaminophen-induced acute liver injury via free cholesterol accumulation in LSECs, demonstrating a novel role of free cholesterol as a metabolic factor in TLR9 signal regulation and pathologies of acetaminophen-induced liver injury. Therapeutic approaches may target this pathway. Lay summary: High cholesterol intake exacerbated acetaminophen-induced acute liver injury via the accumulation of free cholesterol in the endolysosomes of liver sinusoidal endothelial cells. This accumulation enhanced Toll-like receptor 9 signaling via impairment of its membrane trafficking mechanism. Thus, free cholesterol accumulation, as an underlying metabolic factor, exacerbated the pathology of acetaminophen-induced liver injury through activation of the TLR9/inflammasome pathway.
肥胖是急性肝衰竭的一个风险因素，但发病机制尚不完全清楚。高胆固醇（HC）的摄入，这通常是肥胖的基础，被认为在该机制中起作用。我们旨在阐明 HC 饮食对乙酰氨基酚诱导的急性肝损伤的影响，这是美国最常见的急性肝衰竭的原因。
C57BL/6 Toll 样受体 9（TLR9）敲除（Tlr9）小鼠及其 TLR9 同窝仔鼠喂养 HC 饮食 4 周，然后用乙酰氨基酚处理。从小鼠中分离肝窦内皮细胞（LSEC）用于体内和体外分析。
HC 饮食以 TLR9/炎症小体途径依赖性方式加剧了乙酰氨基酚诱导的急性肝损伤。LSEC 在胆固醇负荷诱导的加剧中起主要作用。LSEC 内溶酶体中的游离胆固醇积累增强了 TLR9 介导的信号转导，从而通过激活 TLR9/炎症小体途径加剧了乙酰氨基酚诱导的肝损伤的病理学。LSEC 内溶酶体中游离胆固醇的积累诱导 Rab7 膜转运再循环机制的功能障碍，从而破坏 TLR9 从晚期内体向溶酶体的运输。因此，晚期内体中活性 TLR9 的水平增加，从而增强了 LSEC 中的 TLR9 信号。
HC 摄入通过 LSEC 中的游离胆固醇积累加剧了乙酰氨基酚诱导的急性肝损伤，表明游离胆固醇作为代谢因子在 TLR9 信号调节和乙酰氨基酚诱导的肝损伤病理中的新作用。治疗方法可能针对该途径。
高胆固醇的摄入通过肝窦内皮细胞内溶酶体中的游离胆固醇积累加剧了乙酰氨基酚诱导的急性肝损伤。这种积累通过损害其膜转运机制增强了 Toll 样受体 9 信号。因此，游离胆固醇积累作为一种潜在的代谢因素，通过激活 TLR9/炎症小体途径加剧了乙酰氨基酚诱导的肝损伤的病理。
