Roles Of Endoplasmic Reticulum Stress In Liver Steatosis Of Type 2 Diabetic And Atherosclerosis Mouse Model

Nonalcoholic fatty liver disease (NAFLD) is a relatively new hepatic sequela of obesity and type 2 diabetes mellitus (T2DM). The pathogenesis of liver injury and disease progression in NAFLD, however, is poorly understood. To investigate the potential role of endoplasmic reticulum stress (ERS) in development of liver steatosis, T2DM and atherosclerosis mouse model has been established by STZ injection combined with fed high fat diet on low density lipoprotein receptor deficient (LDLR-/-) mouse background. The differential expression of ERS and lipid metabolism related genes in the liver of T2DM and non-T2DM (ND) mice were measured with real-time quantitative RT-PCR method. Plamsma total cholesterol (TC), triglyceride (TG), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), free fat acid (FFA), alanine amino transferase (ALT) and aspartate amino transferase (AST) level as well as liver TG, FFA content and morphology were also analyzed.The T2DM mice exhibited severe hyperglycemia, insulin resistance, and showed substantial increases in TC, TG, LDL-C, HDL-C and liver TG and FFA content compared with non-T2DM mice from the age of 10 weeks old (P<0.01). The T2DM mice also have increased serum ALT level at the age of 14 weeks and increased AST level at 10 weeks old (P<0.01). In addition, these mice exhibited accelerated hepatic steatosis, associated with increased glucose regulated protein 78 (GRP78), glucose regulated protein 94 (GRP94), activating transcription factor 4 (ATF4), X-box binding protein 1 (XBP1), C/EBP homologous protein (CHOP) and tribbles-related protein 3 (TRB3) mRNA levels, as markers of ERS, compared with ND group mice at the age of 10, 18, 34 weeks old (P<0.05). Effects on apoB100 secretion, which is required for very low density lipoprotein (VLDL) assembly, were parabolic. It was elevated at the age of 10 weeks (P<0.01), but later it was decreased thereafter in T2DM mice (P<0.05). The abnormal of lipid metabolism caused increased de novo lipogenesis associated genes, for example glycogen synthase kinase3β(GSK3β), sterol regulatory element binding proteins-1c (SREBP-1c), carbohydrate response element–binding protein (ChREBP), acetyl CoA carboxylaseα(ACCα), fatty acid synthase (FAS), stearoyl-CoA desaturase-1 (SCD-1), glyceraldehyde 3-phosphate acyltransferase (GPAT) and apoB100 from 10 weeks old (P<0.05). Transcript levels of liver X receptorα(LXRα) and acetyl CoA carboxylaseβ(ACCβ), were higher at 10 and 18 weeks old (P <0.05). Meanwhile, the expressions of genes about ERS associated degradation for examples ER degradation enhancer, mannosidase alpha-like 1 (EDEM1), DnaJ (Hsp40) homolog, subfamily C, member 3 (P58IPK) and heat shock protein 70 (Hsp70) were significantly higher in the T2DM group mice compared with ND group at the age of 18 and 34 weeks (P <0.05), which were responsible for the decreased level of apoB100 secretion and aggravated liver steatosis.These data suggest that the ERS plays a central role in the development of liver steatosis in the T2DM mouse model by the way of increased de novo lipogenesis and decreased secretion of apoB100.