Abstract
Diabetes is commonly associated with liver lipid metabolism disorders. AMP-activated protein kinase (AMPK) has a key role in regulating lipid metabolism. Grape seed procyanidin B2 (GSPB2), a natural polyphenol polymer, ameliorates mitochondrial dysfunction and inhibits oxidative stress or apoptosis via AMPK pathways. In the present study, the hypothesis that GSPB2 treatment may ameliorate liver lipid metabolic disorders by activating AMPK and downstream pathways was tested in diabetic mice. Db/m mice were used as controls, and diabetic db/db mice were randomly divided into 2 groups for treatment: Vehicle and GSPB2 (30mg/kg/day for 10weeks). Animals were weighed every week. Fasting blood was collected prior to sacrifice to measure fasting blood glucose (FBG), triglycerides (TG) and total cholesterol (TC). Hepatic TG and free fatty acid (FFA) levels were analyzed. Hepatic sections were examined by light microscopy following hematoxylin and eosin staining. The expression of hepatic AMPK, phosphorylated acetyl‑CoA carboxylase (ACC), carnitine palmitoyl transferase 1 (CPT1) and 4‑hydroxynonenal (4‑HNE) was measured by western blot analysis. Liver mitochondria were isolated to assess electron transport complex I (CI), complex II (CII) and complex IV by high-resolution respirometry. The results demonstrated that GSPB2 significantly decreased body weight and serum TG, TC and FFA levels, but not FBG levels in diabetic mice. GSPB2 visibly decreased lipid droplet accumulation in the liver and significantly reduced hepatic TG and FFA levels. In diabetic mice, GSPB2 restored liver AMPK and ACC phosphorylation, increased CPT1 protein expression, ameliorated lipid peroxidation damage, which was assessed by comparing 4‑HNE levels, and partially restored the damaged mitochondrial respiratory capacity of CI and CII in the liver. In conclusion, long‑term oral treatment with GSPB2 may benefit hepatic lipid metabolism disorders, potentially by decreasing hepatic lipid synthesis and increasing hepatic FFA β‑oxidation via the AMPK‑ACC pathway.
Highlights
Diabetes has become a global health epidemic
fasting blood glucose (FBG) was significantly higher in DM and DMT mice compared with control mice (P0.05; Fig. 1B)
GSPB2 treatment significantly decreased the TG, total cholesterol (TC) and free fatty acid (FFA) levels compared with the DM group, serum TG and FFA levels remained higher compared with control mice in the DMT group (Fig. 1C‐E)
Summary
Diabetes has become a global health epidemic. In 2012, the economic burden of diagnosed diabetes was estimated to be in excess of $245 billion in the United States alone, representing a >40% increase in cost over 2007 estimates, with most of this burden attributed to the treatment and management of diabetes [1,2]. Diabetes is commonly associated with lipid metabolism disorders and abnormal serum lipid levels, which accelerate the progression of diabetes and lead to atherosclerosis and cardiovascular diseases [3,4], the primary causes of death in patients with diabetes. Fatty liver disease is highly prevalent in patients with type 2 diabetes mellitus [6]. Increased circulating levels of free FAs (FFAs) lead to increased delivery of FFAs to the liver, which subsequently drive the synthesis of excess triglycerides (TG) in the liver; the accumulation of excess liver fat is worsened by impaired hepatic FA oxidation in patients with type 2 diabetes [5]. Ameliorating hepatic lipid metabolism disorders may be an effective way of improving whole‐body lipid metabolism, decelerating the progression of diabetes complications and improving the prognosis of patients with diabetes
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