Cardiometabolic and Microbiome Research Unit, Department of Physiology, College of Medicine and Health Sciences, Afe Babalola University, Ado-Ekiti, 360101, Nigeria.
Cardiometabolic and Microbiome Research Unit, Department of Physiology, College of Medicine and Health Sciences, Afe Babalola University, Ado-Ekiti, 360101, Nigeria.
Biomed Pharmacother. 2020 Aug;128:110226. doi: 10.1016/j.biopha.2020.110226. Epub 2020 May 24.
Hepatic lipid dysregulation with consequent lipotoxicity remains critical in the progression of non-alcoholic fatty liver disease, a rising prevalent complication of diabetes mellitus particularly type 2 diabetes. Diabetes-associated hepatic complications are among the leading causes of liver-related morbidity and mortality worldwide. Short chain fatty acids (SCFAs) have been demonstrated to regulate glycemic metabolism but its effect on diabetes-driven hepatic perturbation is unknown. This study is therefore designed to investigate the effect of SCFAs, acetate on diabetes-characterised hepatic lipotoxicity, and plausible involvement of histone deacetylase (HDAC) activity.
Adult male Wistar rats (230-260 g) were allotted into groups (n = 6/group) namely: control (vehicle; p.o.), sodium acetate (SAT)-treated (200 mg/kg), diabetic with/without SAT groups. Diabetes was induced by intraperitoneal injection of streptozotocin 65 mg/kg after a dose of nicotinamide 110 mg/kg.
Data from diabetic animals showed increased fasting glycemia and insulinemia, decreased insulin sensitivity and body weight with increased relative hepatic mass. It also revealed increased hepatic lipid, serum/hepatic malondialdehyde, tissue necrosis factor-α, uric acid, aspartate transaminase, alanine aminotransferase and decreased glutathione content with elevated hepatic HDAC. Histologically, the hepatic tissue was characterised with disrupted architecture, inflammation of central vein and foci of periportal and sinusoidal cellular infiltration. However, these alterations were attenuated by sodium acetate.
The study demonstrates that diabetes mellitus drives hepatic lipotoxicity, characterised with lipid accumulation, excessive lipid peroxidation, pro-inflammation, depleted glutathione content and accompanied by increased HDAC activity. Besides, the study suggests that acetate ameliorates diabetes-associated hepatic lipotoxicity through HDAC suppression and enhancement of insulin sensitivity.
非酒精性脂肪性肝病（NAFLD）的进展过程中，肝脂质失调导致脂毒性仍然是关键，这是糖尿病（尤其是 2 型糖尿病）的一种常见并发症。与糖尿病相关的肝并发症是全球导致肝相关发病率和死亡率的主要原因之一。短链脂肪酸（SCFAs）已被证明可调节血糖代谢，但它对糖尿病驱动的肝扰动的影响尚不清楚。因此，本研究旨在研究 SCFA 乙酸盐对糖尿病特征性肝脂毒性的影响，以及组蛋白去乙酰化酶（HDAC）活性的可能参与。
将成年雄性 Wistar 大鼠（230-260g）分为以下几组（n=6/组）：对照组（载体；口服）、醋酸钠（SAT）处理组（200mg/kg）、糖尿病加/不加 SAT 组。糖尿病通过腹腔注射链脲佐菌素 65mg/kg 后给予烟酰胺 110mg/kg 诱导。
糖尿病动物的数据显示空腹血糖和胰岛素升高，胰岛素敏感性降低，体重减轻，肝相对质量增加。还显示肝脂质、血清/肝丙二醛、组织肿瘤坏死因子-α、尿酸、天门冬氨酸转氨酶、丙氨酸氨基转移酶增加，肝谷胱甘肽含量降低，肝 HDAC 升高。组织学上，肝组织的特征是结构破坏、中央静脉炎症和门管区和窦状隙细胞浸润灶。然而，这些改变被醋酸钠减弱。
该研究表明，糖尿病导致肝脂毒性，其特征是脂质积累、脂质过氧化过度、炎症前状态、谷胱甘肽含量减少，并伴有 HDAC 活性增加。此外，该研究表明，乙酸盐通过抑制 HDAC 和增强胰岛素敏感性来改善与糖尿病相关的肝脂毒性。
