AKR1B1 drives hyperglycemia-induced metabolic reprogramming in NAFLD-associated carcinogenesis and progression of hepatocellular carcinoma
Authors: NP Syamprasad , Jain Siddhi , Rajdev Bishal , Panda Samir Ranjan , Kumar Gangasani Jagadeesh , Shaik Khaja Moinuddin , Shantanu PA , Challa Veerabhadra Swamy , Vaidya Jayathirtha Rao , Tripathi Dinesh Mani , Naidu VGM 
Published: January 2023

Abstract
Objective
Emergent epidemiological evidence suggests that the progression of NAFLD/NASH-associated HCC positively correlates with the patient's glycemic index. However, the mechanism behind this progressive pathological alteration is poorly understood. It has shown that the polyol pathway master regulator, AKR1B1 is over-expressed in hyperglycemia and responsible for most of diabetic complications. Hence in the present study, we have investigated the role of AKR1B1 in metabolic switching associated with NAFLD/NASH and in the progression of HCC.
Methods
The expression of AKR1B1 in NAFL/NASH, HCC, and HCC with diabetes mellitus patient's liver and plasma were estimated. The role of AKR1B1 in the metabolic switching of HCC cell lines was assessed through media conditioning and lentiviral transfection. Standard inhibitor epalrestat or investigational drug NARI-29 (4-((Z)-5-((Z)-2-Cyano-3-phenylallylidene)-4-oxo-2-thioxothiazolidin-3-yl) benzoic acid) was utilized to elucidate the effect of AKR1B1 inhibition in hepatocarcinogenesis. A proteomic approach was applied for an in-depth investigation of the involved metabolic pathway and to evaluate the therapeutic efficacy of pharmacological inhibitors. Preclinically, a high fructose diet (HFrD) fed in combination with a diethyl nitrosamine (DEN) induced mouse model was developed to investigate the role of AKR1B1 in the hyperglycemia-mediated metabolic switching in the pathobiology of NAFLD and its progression to HCC.
Results
A significant increase in the expression of AKR1B1 was observed in NAFL/NASH, HCC, and HCC-DM tissue samples compared to non-involved adjacent tissues indicating its role in the disease progression. Moreover, a statistically significant elevation of AKR1B1 was observed in NAFLD, NAFLD-associated HCC, and HCC-DM plasma samples compared to normal control. Mechanistically, Invitro assays revealed that AKR1B1 modulates the Warburg effect, mitochondrial dynamics, TCA cycle, and lipogenesis to promote hyperglycemia-mediated fatty liver and cancer progression. A pathologically increased expression of AKR1B1 was observed in experimental NAFL-HCC, and expression was positively correlated with high blood glucose levels. HFrD + DEN-treated animals also exhibited statistically significant elevation of metabolic markers and carcinogenesis markers. However, AKR1B1 inhibition with EPS or NARI-29 has inhibited cellular metabolism in vitro and in vivo models.
Conclusion
Pathological AKR1B1 modulates hepatic glucose metabolism to promote NAFLD-associated hepato-carcinogenesis. Aldose reductase inhibition modulates glucose metabolism to prevent the pre-cancerous hepatocyte formation. Hence EPS and NARI-29 could be promising AKR1B1 inhibitors for controlling aberrant metabolism and treating NAFLD-associated HCC.