Abstract 18829: Inhibiting Bone Morphogenetic Protein Signaling Reduces Diabetes-Associated Non-Alcoholic Fatty Liver Disease Independent of Plasma Lipid Levels

Abstract

Background: Non-alcoholic fatty liver disease (NAFLD) is associated with diabetes and atherosclerotic heart disease and its presence predicts worse cardiovascular outcomes. However, the mechanisms responsible for NAFLD remain unclear and no targeted medical therapy exists. Given the essential role for bone morphogenetic protein (BMP) signaling in the development of atherosclerosis and related inflammation, we hypothesized that BMP signaling is upregulated in livers of diabetic mice (db/db) known to develop NAFLD and that pharmacologic inhibition of BMP signaling may reduce fatty liver disease.

Methods: Livers from adult male wild-type (WT) and db/db mice were harvested to quantify Smad 1/5 phosphorylation and Id1 gene expression (markers of BMP signaling). Diabetic mice were treated with either vehicle or the small molecule BMP type I receptor inhibitor, LDN-193189 (LDN, 3 mg/kg twice daily IP), for 28 days. Plasma samples were collected, and livers were harvested for biochemical and histological examination. Hepatic fat content was estimated using colorimetric intensity quantification of hematoxylin & eosin stains.

Results: Smad 1/5 phosphorylation and Id1 mRNA levels were 2.5- and 3.0-fold greater in livers of db/db mice than in WT mice (P=0.003 and 0.006, respectively; n=8 per group). Treatment of db/db mice with LDN decreased liver Smad 1/5 phosphorylation and Id1 mRNA levels associated with a 49% reduction in hepatic fat accumulation (P=0.017; see Figure). Furthermore, plasma alanine aminotransferase levels were less in LDN-treated mice than in vehicle-treated mice (mean ± SEM 194 ± 68 vs. 583 ± 153 U/L, n=7 per group, P=0.048); however, there was no difference in plasma cholesterol or triglyceride levels.

Conclusions: Increased BMP signaling contributes to the development of NAFLD in a diabetic mouse model, independent of plasma lipid levels. Pharmacologic BMP inhibition may represent a novel therapy for NAFLD.