Quantitative proteomics study on the protective mechanism of phlorizin on hepatic damage in diabetic db/db mice

Abstract

Abstract. Although phlorizin has been used in the treatment of diabetes mellitus for over 100 years, the underlying molecular mechanisms have not been fully elucidated. This study investigated the effect of phlorizin on body weight, blood glucose, blood triglycerides (TG), blood total cholesterol (TC), as well as overall changes in protein expression in db/db diabetic mouse liver. Phlorizin significantly decreased body weight gain and the levels of glucose, TC and TG in blood. Isobaric tag for relative and absolute quantitation (iTRAQ) quantitative proteomics profiling revealed that phlorizin interfered with the processes of carbohydrate metabolism, fatty acid biosynthesis and β-oxidation, cholesterol biosynthesis, and free radical scavenging by affecting the expression of key proteins in these processes. Ingenuity Pathway Analysis successfully established several pathway networks, in which many differentially expressed proteins were involved. The differential expression of several proteins was validated by western blotting. Our study offers important information on the mechanism of phlorizin treatment in diabetes mellitus, particularly in the liver. IntroductionType 2 diabetes is one of the most common endocrine diseases in developed countries, which is caused by absolute or relative deficiencies in insulin secretion or insulin action (1). Chronic hyperglycemia is the major biochemical alteration in type 2 diabetes. Moreover, individuals with type 2 diabetes usually display a marked disruption of lipid metabolism, with an abnormal accumulation of fat in various tissues including the liver (2). Hyperglycemia and hyperlipidemia not only impair β-cell function and increase insulin resistance in peripheral tissues, such as the muscle, liver, and adipose tissue (3,4), but also induce oxidative stress reactions, which cause initiation and progression of diabetes-related diseases (5,6). Consequently, regulation of dyslipidemia and reduction in oxidative stress have been regarded as important treatment methods for alleviating diabetes and its complications.Phlorizin (glucose,1-[2-(β.D-glucopyranosyloxy)-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)-1-propanone) is a member of the chalcone class of organic compounds and is mainly distributed in the plants of the genus Malus (7). Phlorizin has multiple pharmacological activities, such as anti-oxidative, estrogenic and anti-estrogenic activities, memory improvement and cardioprotective activities (8-11). Reports show that phlorizin inhibits intestinal glucose uptake and renal glucose reabsorption by inhibiting the sodium D-glucose cotransporter (10,12). Phlorizin has been reported to normalize the effects of insulin on glucose metabolism in the liver and other peripheral tissues (13). However, little is known regarding the effect of phlorizin on hepatic damage associated with type 2 diabetes.The rapidly emerging field of quantitative proteomics provides a powerful technique -isobaric tag for relative and absolute quantitation (iTRAQ) labeling combined with liquid chromatograph...

Apple phlorizin attenuates oxidative stress inDrosophila melanogaster

“…Phlorizin increased the expression of cnc gene, Keap1 gene, and cnc target gene GclC, which encodes glutamate-cysteine ligase and whose overexpression is known to prolong the life span of flies (Karim, Taniguchi, & Kobayashi, 2015). The data in the present study were consistent with Lu's findings that the mRNA expression of Mn-SOD, CAT, GPX1, GPX4, and peroxiredoxin 3 increased 1.88-to 4.19fold in diabetic db/db mice treated with phlorizin (Lu et al, 2012).…”

Phenolic Composition and Antioxidant Activity ofMalus domesticaLeaves

“…Phloridzin ability to reverse glucotoxicity and reduce blood glucose levels without increasing body weight determines its benefits in prophylaxis and treatment of type 2 diabetes [ 69 – 71 ]. Phloridzin reduces body weight by blocking the absorption and resorption of glucose [ 72 , 73 ], and the weight loss is one of the most important type 2 diabetes prevention methods [ 74 , 75 ]. Phloridzin consumption to reduce glucose concentration in blood plasma does not cause body fluid loss and hypoglycemia risk [ 66 , 76 ].…”

Apigenin Ameliorates Dyslipidemia, Hepatic Steatosis and Insulin Resistance by Modulating Metabolic and Transcriptional Profiles in the Liver of High-Fat Diet-Induced Obese Mice

“…The reactions of the TCA cycle generate NADH and FADH2, which are in turn used by the OXPHOS pathway to generate ATP [ 42 ]. The mRNA expression of Elovl2, which is involved in the elongation required for the synthesis of docosahexaenoic acid, was reduced in the livers of obese subjects, and an intervention to improve hepatic steatosis and diabetes upregulated hepatic Elovl2 expression along with hepatic fatty acid oxidation [ 43 , 44 ]. Since the synthesis of docosahexaenoic acid from linolenic acid requires one round of peroxisomal β-oxidation in addition to elongation and desaturation [ 45 ], the observed upregulation of Elovl2 may be related to the upregulated expression of peroxisomal fatty acid oxidation genes, such as Ehhadh.…”