Allopurinol ameliorates high fructose diet induced hepatic steatosis in diabetic rats through modulation of lipid metabolism, inflammation, and ER stress pathway

Abstract

Excess fructose consumption contributes to development obesity, metabolic syndrome, and nonalcoholic fatty liver disease (NAFLD). Uric acid (UA), a metabolite of fructose metabolism, may have a direct role in development of NAFLD, with unclear mechanism. This study aimed to evaluate role of fructose and UA in NAFLD and explore mechanisms of allopurinol (Allo, a UA lowering medication) on NAFLD in Otsuka Long-Evans Tokushima Fatty (OLETF) rats fed a high fructose diet (HFrD), with Long-Evans Tokushima Otsuka (LETO) rats used as a control. There were six groups: LETO, LETO-Allo, OLETF, OLETF-Allo, OLETF-HFrD, and OLETF-HFrD-Allo. HFrD significantly increased body weight, epididymal fat weight, and serum concentrations of UA, cholesterol, triglyceride, HbA1c, hepatic enzymes, HOMA-IR, fasting insulin, and two hour-glucose after intraperitoneal glucose tolerance tests, as well as NAFLD activity score of liver, compared to the OLETF group. Allopurinol treatment significantly reduced hepatic steatosis, epididymal fat, serum UA, HOMA-IR, hepatic enzyme levels, and cholesterol in the OLETF-HFrD-Allo group. Additionally, allopurinol significantly downregulated expression of lipogenic genes, upregulated lipid oxidation genes, downregulated hepatic pro-inflammatory cytokine genes, and decreased ER-stress induced protein expression, in comparison with the OLETF-HFrD group. In conclusion, allopurinol ameliorates HFrD-induced hepatic steatosis through modulation of hepatic lipid metabolism, inflammation, and ER stress pathway. UA may have a direct role in development of fructose-induced hepatic steatosis, and allopurinol could be a candidate for prevention or treatment of NAFLD.

Dietary Ferulic Acid Ameliorates Metabolism Syndrome-Associated Hyperuricemia in Rats via Regulating Uric Acid Synthesis, Glycolipid Metabolism, and Hepatic Injury

“…It has been reported that ferulic acid could reduce adipogenesis, stored lipid content in adipose tissue and adipose tissue expansion, and stimulate white-fat browning via regulating the expression of related genes, revealing the anti-obesity effect of ferulic acid ( 37 – 39 ). We found that allopurinol, a XO inhibitor, also exerted anti-obesity capacity, which was in line with the studies of Cho et al ( 40 ) and Zhang et al ( 41 ).…”

“…The circulatory lipids like FFA from adipocytes can be taken up by the hepatocytes for the synthesis of TG and other lipids, and fructose metabolism can also lead to lipid deposition in the live, bringing about non-alcoholic fatty liver and then progress to non-alcoholic steatohepatitis, fibrosis, cirrhosis, hepatocellular cancer, and liver failure (49,52,53). In the present study, we discovered that rats treated with ferulic acid and allopurinol showed less hepatic steatosis than rats in the model group, embodied in lower hepatic TG, TC, and FFA contents (Figures 3D-F), likely though suppressing de novo lipogenesis and promoting β-oxidation of FFA (26,39,40).…”

Diosgenin Ameliorated Type II Diabetes-Associated Nonalcoholic Fatty Liver Disease through Inhibiting De Novo Lipogenesis and Improving Fatty Acid Oxidation and Mitochondrial Function in Rats

“…The IRE1α-XBP1 pathway can trigger de novo lipogenesis (DNL) by SREBP1 and its downstream genes [ 38 ]. Cho et al [ 39 ] suggested that allopurinol relieved hepatic steatosis induced by high-fructose diet through the modulation of ER stress via the IRE1 pathway. Wu et al [ 40 ] showed that Patchouli alcohol attenuated ER stress and hepatic steatosis through inhibiting the activation of PERK and IRE1 pathways in HFD-fed rats.…”

Allopurinol Use and the Risk of Type 2 Diabetes Mellitus: A Meta-Analysis of Cohort Studies

“…The animal models disclosed that allopurinol could ameliorate insulin resistance in rats and mice. [23][24][25][26] Previous clinical research also showed allopurinol could ameliorate insulin resistance in humans. 8 The study of Fang et al included in our meta-analysis disclosed a reduced HR for T2DM associated with allopurinol use.…”