thapsigargin and 3-aminoisobutyric-acid

β-aminoisobutyric acid (BAIBA) is a nature thymine catabolite, and contributes to exercise-induced protection from metabolic diseases. Here we show the therapeutical effects of BAIBA on hepatic endoplasmic reticulum (ER) stress and glucose/lipid metabolic disturbance in diabetes. Type 2 diabetes was induced by combined streptozotocin (STZ) and high-fat diet (HFD) in mice. Oral administration of BAIBA for 4 weeks reduced blood glucose and lipids levels, hepatic key enzymes of gluconeogenesis and lipogenesis expressions, attenuated hepatic insulin resistance and lipid accumulation, and improved insulin signaling in type 2 diabetic mice. BAIBA reduced hepatic ER stress and apoptosis in type 2 diabetic mice. Furthermore, BAIBA alleviated ER stress in human hepatocellular carcinoma (HepG2) cells with glucosamine-induced insulin resistance. Hepatic AMPK phosphorylation was reduced in STZ/HFD mice and glucosamine-treated HepG2 cells, which were restored by BAIBA treatment. The suppressive effects of BAIBA on glucosamine-induced ER stress were reversed by knockdown of AMPK with siRNA. In addition, BAIBA prevented thapsigargin- or tunicamycin-induced ER stress, and tunicamycin-induced apoptosis in HepG2 cells. These results indicate that BAIBA attenuates hepatic ER stress, apoptosis and glucose/lipid metabolic disturbance in mice with type 2 diabetes. AMPK signaling is involved to the role of BAIBA in attenuating ER stress.

Topics: Administration, Oral; Aminoisobutyric Acids; AMP-Activated Protein Kinases; Animals; Apoptosis; Blood Glucose; Blotting, Western; Carbohydrate Metabolism; Cholesterol; Diabetes Mellitus, Experimental; Diet, High-Fat; Endoplasmic Reticulum Stress; Glucosamine; Hep G2 Cells; Humans; Immunohistochemistry; Insulin Resistance; Lipid Metabolism; Liver; Mice; Phosphorylation; Real-Time Polymerase Chain Reaction; RNA Interference; RNA, Small Interfering; Signal Transduction; Thapsigargin; Triglycerides; Tunicamycin