Caffeic acid dimethyl ether alleviates alcohol-induced hepatic steatosis via microRNA-378b-mediated CaMKK2-AMPK pathway

Abstract

Alcoholic liver disease (ALD), with its increasing morbidity and mortality, has seriously and extensively affected the health of people worldwide. Caffeic Acid Dimethyl Ether (CADE) significantly inhibits alcohol-induced hepatic steatosis in vivo through AMP-activated protein kinase (AMPK) pathway, but its in-depth mechanism remains unclear. This work aimed to clarify further mechanism of CADE in improving hepatic lipid accumulation in ALD through the microRNA-378b (miR-378b)-mediated Ca2+/calmodulin-dependent protein kinase kinase 2 (CaMKK2)-AMPK signaling pathway. Here, we reported that the hepatic or serum triglyceride (TG), total cholesterol (TC), alanine aminotransferase (ALT), and aspartate transaminase (AST) levels were sharply escalated by ethanol while prominently decreased by CADE. Ethanol sharply up-regulated miR-378b expression while CADE effectively prevented the elevation of miR-378b in vivo . And treatment of CADE surely increased mRNA and protein expression of CaMKK2 as a kinase of AMPK and reduced lipid accumulation in the livers of alcohol-fed C57BL/6 mice. MiR-378b escalation exacerbated hepatic steatosis and inhibited CaMKK2-AMPK signaling, while miR-378b deficiency alleviated lipid accumulation and activated the CaMKK2 cascade. Furthermore, CADE alleviated the lipid deposition and reversed the disorder of CaMKK2-AMPK signaling pathway induced by miR-378b over-expression. However, knockdown of miR-378b eliminated the beneficial effect of CADE on lipid metabolism. In brief, our results showed that CADE ultimately improved hepatic lipid deposition by regulating the CaMKK2-AMPK signaling pathway through miR-378b.

Sex-specific transcriptional rewiring in the brain of Alzheimer’s disease patients

“…Long-term alcohol consumption promotes the degradation of HDAC5 and may increase vulnerability to cocaine addiction ( Griffin Jr. et al, 2017 ). CAMKK2 is involved in ethanol-induced hepatic steatosis, and treatment with caffeic acid, a phytochemical in coffee, increases its mRNA and protein expression, thereby reducing alcohol-mediated damage in mice ( Lu et al, 2022 ). Furthermore, CAMKK2 is associated with amyloid beta-induced neurotoxicity resulting in dendritic spine loss, and its inhibition protected hippocampal neurons against neurotoxicity in a transgenic mouse model of AD ( Mairet-Coello et al, 2013 ).…”

Caffeic Acid Dimethyl Ether Ameliorates Excessive Glucose and Lipid-Induced Insulin Secretion Dysfunction in Pancreatic Beta-Cells through the miR-378b–PI3K–AKT Pathway

“…Mice with fasting blood glucose >11.1 mM were defned as T2DM mice [32,33]. Te T2DM mice were randomly divided into four groups: the diabetic group (DC), the diabetic + 10 mg/kg glibenclamide group (DC + Gliben), the diabetic + 5 mg/kg CADE group (DC + CADE-L), and the diabetic + 10 mg/kg CADE group (DC + CADE-H) [31]. Mice were gavaged with CADE, glibenclamide or 0.5% CMC-Na once daily for six weeks.…”

“…Cafeic acid dimethyl ether (CADE), also known as methyl ferulic acid, is a bioactive monomer extracted from traditional Chinese herbs [30]. It can improve insulin resistance in mice with alcoholic fatty liver [21] and alleviate hepatic steatosis [31]. However, it remains unclear what efect CADE has on impaired insulin secretion in diabetic patients.…”