2119-P: AKR1B10 Is Upregulated in Nonalcoholic Fatty Liver Disease and Is Regulated by Fatty Acid Loading in Hepatocytes and Hepatic Stellate Cells

Abstract

Type 2 diabetes (T2D) and obesity are associated with fat accumulation in the liver, which is commonly diagnosed as nonalcoholic fatty liver disease (NAFLD). Not only do individuals with T2D have an increased risk of developing the disease, but patients with NAFLD are also at greater risk for developing T2D, and the majority of patients with NAFLD are overweight or obese. Hepatic lipid accumulation has been proposed as a cause, rather than a consequence, of hepatic insulin resistance, but the molecular mechanisms by which this occurs are not yet known. We previously observed abundant expression of aldo-keto reductase family 1 member 10 (AKR1B10) in obese NAFLD patients with advanced liver fibrosis using RNA-sequencing. The goals of this study were to measure AKR1B10 expression across the histological spectrum of NAFLD and elucidate factors that regulate AKR1B10 expression in cultured liver cells. We found that hepatic AKR1B10 expression was increased 6-fold, 19-fold, and 50-fold in NAFLD patients with steatosis, inflammation, and fibrosis compared to those with normal liver histology (P<0.05). We next treated human hepatocytes and hepatic stellate cells with 100 µM palmitate for 24 hours and found a 1.5-fold and 8-fold upregulation, respectively, in AKR1B10 expression compared to vehicle-treated cells. These results show that AKR1B10, which functions to reduce retinals to retinols in the liver, is increased across the NAFLD spectrum and upregulated in key liver cells in response to lipid loading. Studies to investigate the relationship between AKR1B10 expression and lipid-loading in NAFLD are ongoing. Disclosure B. Davis: None. D.M. Wilhelmsen: Stock/Shareholder; Self; Not sure of company name. Stock/Shareholder; Spouse/Partner; Not sure-. A. Hanson: None. J. DiStefano: None. Funding National Institutes of Health (DK091601)