Department of Pharmacology, Second Military Medical University (Naval Medical University), Shanghai 200433, China.
Cells. 2023 Feb 10;12(4):568. doi: 10.3390/cells12040568.
Nicotinamide phosphoribosyltransferase (Nampt) is the rate-limiting enzyme in the salvage pathway of nicotinamide adenine dinucleotide (NAD) biosynthesis. Thus far, hepatic Nampt has not been extensively explored in terms of its effects on serum lipid stability and liver lipids metabolism. In this study, hepatocyte-specific Nampt knockout (HC-Nampt) mice were generated by Cre/loxP system. Nampt mRNA expression was reduced in the liver, but not in other tissues, in HC-Nampt mice compared with wild-type (WT) mice. Hepatic Nampt deficiency had no effect on body weight and fasting blood glucose, and it did not induce atherosclerosis in mice under both normal chow diet (NCD) and high fat diet (HFD). At baseline state under NCD, hepatic Nampt deficiency also did not affect liver weight, liver function index, including alanine aminotransferase, aspartate aminotransferase, albumin and alkaline phosphatase, and serum levels of lipids, including triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and non-esterified fatty acids (NEFA). However, under HFD, deficiency of hepatic Nampt resulted in increased liver weight, liver function index, and serum levels of TG, TC, HDL-C, and NEFA. Meanwhile, histopathological examination showed increased fat accumulation and fibrosis in the liver of HC-Nampt mice compared with WT mice. Taken together, our results show that hepatic Nampt deficiency aggravates dyslipidemia and liver damage in HFD fed mice. Hepatocyte Nampt can be a protective target against dyslipidemia and fatty liver.
烟酰胺磷酸核糖基转移酶（Nampt）是烟酰胺腺嘌呤二核苷酸（NAD）生物合成补救途径中的限速酶。迄今为止，肝 Nampt 对血清脂质稳定性和肝脂质代谢的影响尚未得到广泛研究。在本研究中，通过 Cre/loxP 系统生成了肝细胞特异性 Nampt 敲除（HC-Nampt）小鼠。与野生型（WT）小鼠相比，HC-Nampt 小鼠肝脏中的 Nampt mRNA 表达降低，但在其他组织中没有降低。肝 Nampt 缺乏对体重和空腹血糖没有影响，在正常饲料（NCD）和高脂肪饮食（HFD）下也不会诱导小鼠发生动脉粥样硬化。在 NCD 基础状态下，肝 Nampt 缺乏也不会影响肝重、肝功能指标，包括丙氨酸氨基转移酶、天冬氨酸氨基转移酶、白蛋白和碱性磷酸酶，以及血脂水平，包括甘油三酯（TG）、总胆固醇（TC）、高密度脂蛋白胆固醇（HDL-C）、低密度脂蛋白胆固醇（LDL-C）和非酯化脂肪酸（NEFA）。然而，在 HFD 下，肝 Nampt 缺乏导致肝重、肝功能指标和血清 TG、TC、HDL-C 和 NEFA 水平升高。同时，组织病理学检查显示，与 WT 小鼠相比，HC-Nampt 小鼠肝脏中的脂肪堆积和纤维化增加。综上所述，我们的研究结果表明，肝 Nampt 缺乏加重了 HFD 喂养小鼠的血脂异常和肝损伤。肝细胞 Nampt 可能是防治血脂异常和脂肪肝的保护靶标。
