Department of Pharmacology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China.
Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan, 430071, China; Wuhan No.1 Hospital, Wuhan, 430022, China.
Free Radic Biol Med. 2023 Nov 1;208:684-699. doi: 10.1016/j.freeradbiomed.2023.09.026. Epub 2023 Sep 22.
Epidemiological evidence has revealed that non-alcoholic fatty liver disease (NAFLD) harbors an intrauterine origin. Autophagy is known to be involved in the protective mechanism in the development of adult NAFLD, but whether it engages in the occurrence of fetal-originated NAFLD remains unclear. In this study, a rat model of fetal-originated NAFLD was established by giving a high-fat diet or chronic stress after birth on prenatal caffeine exposure (PCE) male offspring. The alterations of liver morphologic analysis, lipid metabolism, and autophagy before and after birth were determined to confirm autophagy mechanism, NAFLD susceptibility, and intrauterine origin in PCE male adult offspring. Our results revealed that PCE-induced intrauterine high concentration of corticosterone exposure blocked autophagic flux by inhibiting cathepsin D expression in hepatocytes, leading to β-oxidation inhibition and lipid accumulation in the liver. Moreover, high concentration of corticosterone upregulated miR-665 by activating the glucocorticoid receptor to suppress cathepsin D, thus causing lysosomal degradation dysfunction and autophagy flux blockade. Notably, hepatic overexpression of cathepsin D could reverse PCE-induced postnatal NAFLD susceptibility in male rat offspring. This study elucidates the epigenetic programming mechanism of intrauterine autophagy-related fetal-originated NAFLD susceptibility, and identifies cathepsin D as its early intervention target, providing an experimental basis for exploring early prevention and treatment strategies for fetal-originated NAFLD.
流行病学证据表明，非酒精性脂肪性肝病（NAFLD）具有宫内起源。自噬被认为参与了成人 NAFLD 的保护机制，但它是否参与胎儿起源的 NAFLD 的发生尚不清楚。在这项研究中，通过在产前咖啡因暴露（PCE）雄性后代出生后给予高脂肪饮食或慢性应激，建立了胎儿起源的 NAFLD 大鼠模型。确定了出生前后肝形态分析、脂质代谢和自噬的变化，以确认自噬机制、PCE 雄性成年后代的 NAFLD 易感性和宫内起源。我们的结果表明，PCE 诱导的宫内高浓度皮质酮暴露通过抑制肝细胞中组织蛋白酶 D 的表达来阻断自噬流，导致β-氧化抑制和肝脏脂质积累。此外，高浓度皮质酮通过激活糖皮质激素受体上调 miR-665 来抑制组织蛋白酶 D，从而导致溶酶体降解功能障碍和自噬流阻断。值得注意的是，肝组织蛋白酶 D 的过表达可逆转 PCE 诱导的雄性大鼠后代出生后 NAFLD 的易感性。本研究阐明了宫内自噬相关胎儿起源的 NAFLD 易感性的表观遗传编程机制，并确定组织蛋白酶 D 为其早期干预靶点，为探索胎儿起源的 NAFLD 的早期预防和治疗策略提供了实验依据。
