ABSTRACT
Anterior gradient 2 (AGR2), a protein disulfide isomerase (PDI), is a multifunctional protein under physiological and pathological conditions. In this study we investigated the roles of AGR2 in regulating cholesterol biogenesis, lipid-lowering efficiency of lovastatin as well as in protection against hypercholesterolemia/statin-induced liver injury. We showed that AGR2 knockout significantly decreased hepatic and serum total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) in mice with whole-body or hepatocyte-specific Agr2-null mutant, compared with the levels in their wild-type littermates fed a normal chow diet (NCD) or high-fat diet (HFD). In contrast, mice with AGR2 overexpression (Agr2/Tg) exhibited an increased cholesterol level. Mechanistic studies revealed that AGR2 affected cholesterol biogenesis via activation of AKT/sterol regulatory element-binding protein-2 (SREBP2), to some extent, in a PDI motif-dependent manner. Moreover, elevated AGR2 led to a significant decrease in the lipid-lowering efficacy of lovastatin (10 mg· kg-1· d-1, ip, for 2 weeks) in mice with hypercholesterolemia (hyperCho), which was validated by results obtained from clinical samples in statin-treated patients. We showed that lovastatin had limited effect on AGR2 expression, but AGR2 was inducible in Agr2/Tg mice fed a HFD. Further investigations demonstrated that drug-induced liver toxicity and inflammatory reactions were alleviated in hypercholesterolemic Agr2/Tg mice, suggesting the dual functions of AGR2 in lipid management and hyperCho/statin-induced liver injury. Importantly, the AGR2-reduced lipid-lowering efficacy of lovastatin was attenuated, at least partially, by co-administration of a sulfhydryl-reactive compound allicin (20 mg· kg-1· d-1, ip, for 2 weeks). These results demonstrate a novel role of AGR2 in cholesterol metabolism, drug resistance and liver protection, suggesting AGR2 as a potential predictor for selection of lipid-lowering drugs in clinic.
Subject(s)
Chemical and Drug Induced Liver Injury, Chronic , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Hypercholesterolemia , Mice , Animals , Lovastatin/pharmacology , Lovastatin/therapeutic use , Lovastatin/metabolism , Hypercholesterolemia/drug therapy , Hydroxymethylglutaryl-CoA Reductase Inhibitors/metabolism , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Chemical and Drug Induced Liver Injury, Chronic/drug therapy , Cholesterol, LDL , Liver/metabolismABSTRACT
Increasing research suggests that mitochondrial defects play a major role in Alzheimer's disease (AD) pathogenesis. We aimed to better understand changes in mitochondria with the development and progression of AD. We compared APPsw/PS1dE9 transgenic mice at 3, 6, 9, and 12 months old as an animal model of AD and age-matched C57BL/6 mice as controls. The learning ability and spatial memory ability of APPsw/PS1dE9 mice showed significant differences compared with controls until 9 and 12 months. Mitochondrial morphology was altered in hippocampus tissue of APPsw/PS1dE9 mice beginning from the third month. 'Medullary corpuscle', which is formed by the accumulation of a large amount of degenerative and fragmented mitochondria in neuropils, may be the characteristic change observed on electron microscopy at a late stage of AD. Moreover, levels of mitochondrial fusion proteins (optic atrophy 1 and mitofusin 2) and fission proteins (dynamin-related protein 1 and fission 1) were altered in transgenic mice compared with controls with progression of AD. We found increased levels of fission and fusion proteins in APP/PS1 mice at 3 months, indicating that the presence of abnormal mitochondrial dynamics may be events in early AD progression. Changes in mitochondrial preceded the onset of memory decline as measured by the modified Morris water maze test. Abnormal mitochondrial dynamics could be a marker for early diagnosis of AD and monitoring disease progression. Further research is needed to study the signaling pathways that govern mitochondrial fission/fusion in AD.
