Department of Gastroenterology, Cleveland Clinic, Cleveland, Ohio.
Merck Research Laboratories, Kenilworth, New Jersey.
Am J Physiol Endocrinol Metab. 2019 Nov 1;317(5):E852-E862. doi: 10.1152/ajpendo.00193.2019. Epub 2019 Sep 10.
Altered lipid metabolism and inflammation are involved in the pathogenesis of both nonalcoholic fatty liver disease (NAFLD) and cardiovascular disease (CVD). Even though high-density lipoprotein (HDL), a CVD protective marker, is decreased, whether HDL metabolism and function are perturbed in NAFLD are currently unknown. We examined the effect of NAFLD and disease severity on HDL metabolism and function in patients with biopsy-proven simple steatosis (SS), nonalcoholic steatohepatitis (NASH), and healthy controls. HDL turnover and HDL protein dynamics in SS ( = 7), NASH ( = 8), and healthy controls ( = 9) were studied in vivo. HDL maturation and remodeling, antioxidant, cholesterol efflux properties, and activities of lecithin-cholesterol ester acyltransferase and cholesterol ester transfer protein (CETP) were quantified using in vitro assays. All patients with NAFLD had increased turnover of both HDL cholesterol (HDLc; 0.16 ± 0.09 vs. 0.34 ± 0.18 days, < 0.05) and apolipoprotein A1 (ApoAI) (0.26 ± 0.04 vs. 0.34 ± 0.06 days, < 0.005) compared with healthy controls. The fractional catabolic rates of other HDL proteins, including ApoAII (and ApoAIV) were higher ( < 0.05) in patients with NAFLD who also had higher CETP activity, ApoAI/HDLc ratio ( < 0.05). NAFLD-induced alterations were associated with lower antioxidant (114.2 ± 46.6 vs. 220.5 ± 48.2 nmol·mL·min) but higher total efflux properties of HDL (23.4 ± 1.3% vs. 25.5 ± 2.3%) (both < 0.05), which was more pronounced in individuals with NASH. However, no differences were observed in either HDL turnover, antioxidant, and cholesterol efflux functions of HDL or HDL proteins' turnover between subjects with SS and subjects with NASH. Thus, HDL metabolism and function are altered in NAFLD without any significant differences between SS and NASH.
改变的脂质代谢和炎症参与了非酒精性脂肪性肝病 (NAFLD) 和心血管疾病 (CVD) 的发病机制。尽管高密度脂蛋白 (HDL) 是心血管疾病的保护标志物，但 NAFLD 中 HDL 的代谢和功能是否受到干扰目前尚不清楚。我们研究了活检证实单纯性脂肪变性 (SS)、非酒精性脂肪性肝炎 (NASH) 和健康对照组患者中 NAFLD 及其严重程度对 HDL 代谢和功能的影响。我们在体内研究了 SS(=7)、NASH(=8)和健康对照组(=9)患者的 HDL 周转率和 HDL 蛋白动力学。使用体外测定法定量测定了 HDL 的成熟和重塑、抗氧化、胆固醇流出特性以及卵磷脂胆固醇酯酰转移酶和胆固醇酯转移蛋白 (CETP) 的活性。所有患有 NAFLD 的患者的 HDL 胆固醇 (HDLc；0.16±0.09 天对 0.34±0.18 天， < 0.05) 和载脂蛋白 A1 (ApoAI；0.26±0.04 天对 0.34±0.06 天， < 0.005) 的周转率均高于健康对照组。载脂蛋白 AII (和 ApoAIV) 等其他 HDL 蛋白的部分分解率也较高 ( < 0.05)，且载脂蛋白 A1/HDLc 比值较高 ( < 0.05)，在患有 NASH 的 NAFLD 患者中，CETP 活性也较高。NAFLD 引起的变化与较低的抗氧化剂 (114.2±46.6 对 220.5±48.2 nmol·mL·min) 但较高的 HDL 总流出特性 (23.4±1.3%对 25.5±2.3%) 相关 (均 < 0.05)，在 NASH 患者中更为明显。然而，在 SS 患者和 NASH 患者之间，在 HDL 周转率、抗氧化剂和 HDL 胆固醇流出功能或 HDL 蛋白周转率方面均未观察到差异。因此，NAFLD 患者的 HDL 代谢和功能发生改变，但 SS 和 NASH 之间无明显差异。
