Combined treatments with metformin and phosphodiesterase inhibitors alleviate nonalcoholic fatty liver disease in high-fat diet fed rats: a comparative study

Abstract

Nonalcoholic fatty liver disease (NAFLD) is an excessive accumulation of fats in the liver resulted in hepatic inflammation and fibrous tissue formation along with insulin resistance. This study was designed to investigate the possible protective effects of metformin alone and in combination with different phosphodiesterase inhibitors (PDEIs). Rats were fed a high-fat diet (HFD) for sixteen weeks to induce NAFLD. Starting from week 12, rats received metformin alone or in combination with pentoxifylline, cilostazol or sildenafil. HFD administration resulted in hepatic steatosis and inflammation in rats. In addition, liver index, body composition index, activities of liver enzymes, and serum lipids deviated from normal. Further, significant elevations were recorded compared to control in terms of serum glucose, insulin and HOMA-IR, oxidative stress parameters, hepatic TNF-α and NF-кB gene expression and iNOS protein expression. Rats treated with metformin showed a significant improvement in the aforementioned parameters. However, the addition of pentoxifylline to metformin treatment synergized its action and produced a fortified effect against HFD-induced NAFLD better than other PDEIs.
 Data from this study indicated that combined treatment of metformin and pentoxifylline had the most remarkable ameliorated effects against HFD-induced NAFLD; further clinical investigations are in-need to approve PDEIs for NAFLD treatment. 

MicroRNA-137-3p Improves Nonalcoholic Fatty Liver Disease through Activating AMPKα

“…Mechanistically, miR-137-3p is directly bound to the 3′-UTR of PDE4D, a cAMP-specific phosphodiesterase, and subsequently increased hepatic cAMP level and PKA activity, thereby activating the downstream AMPK α pathway. Consistently, other findings also proved that the treatment with PDE inhibitors could protect against HFD-induced NAFLD [ 55 , 56 ]. Beyond AMPK α , many other downstream targets of miR-137-3p have been proposed.…”

ANGPTL8 accelerates liver fibrosis mediated by HFD-induced inflammatory activity via LILRB2/ERK signaling pathways

“…We conducted drug screening which revealed that metformin—an FDA-approved biguanide class drug used to treat high blood glucose levels in diabetic patients, which has also been shown to exert other functions [58] , [59] , including anti-tumor and anti-aging effects [58] , [59] , [60] —could inhibit the expression of ANGPTL8 in human HepG2 cells and mouse liver, and conferred protection against HSC activation in the liver as induced by HFD. It has been reported that metformin has an anti-liver fibrosis effect by improving insulin resistance [61] , [62] , but its specific mechanism is not fully understood, especially in the treatment of NAFLD-associated liver fibrosis. Our results showed that metformin inhibited the mRNA expression of ANGPTL8 , and amelioration of HFD-induced liver fibrosis was dependent on inhibition of ANGPTL8 expression in vivo.…”

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“…Serum and plasma were separated and kept at -80 °C until performing the biochemical measurements. Serum insulin was determined using ultrasensitive rat insulin ELISA kit (Crystal Chem Inc., Downers Grove, IL 60515, USA) 18 , serum leptin was measured by rat leptin ELISA kit (Crystal Chem Inc., USA) 19 , serum adiponectin was detected by rat adiponectin ELISA kit (AdipoGen Inc. Korea) 20 , serum glucose level was measured according to the method of Trinder 21 by the enzymatic colorimetric method (Biodiagnostic, Egypt), lipid profile including serum triglycerides (TG), total cholesterol (TC) and high-density lipoprotein cholesterol (HDL-C) were measured by enzymatic colorimetric methods according to Fossati and Prencipe 22 , Allain et al, 23 and Lopes-Virella et al, 24 respectively using Biodiagnostic kits, Egypt, and low-density lipoprotein cholesterol (LDL-C) was calculated according to the method of Friedewald et al, 25 , liver enzymes including alanine aminotransferase (ALT) and aspartate amino-transferase (AST) were measured by enzymatic colorimetric method according to Reitman and Frankel 26 using Biodiagnostic kit (Egypt), and kidney function tests including creatinine was measured according to the method of Murray 27 and urea was measured according to the method of Kaplen 28 by enzymatic colorimetric methods using (Biodiagnostic kit, Giza, Egypt) according to manufacturer's instructions.…”