Int J Med Sci 2018; 15(14):1591-1599. doi:10.7150/ijms.27953 This issue


Phenotypic Alteration of Hepatocytes in Non-Alcoholic Fatty Liver Disease

Hari Vishal Lakhani1, Dana Sharma1, Michael W. Dodrill1, Athar Nawab1, Nitin Sharma1, Cameron Lee Cottrill1, Joseph I. Shapiro1, Komal Sodhi2✉

1. Department of Internal Medicine, Marshall University Joan C Edwards School of Medicine, Huntington, WV, USA;
2. Department of Surgery, Marshall University Joan C Edwards School of Medicine, Huntington, WV, USA.

This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license ( See for full terms and conditions.
Lakhani HV, Sharma D, Dodrill MW, Nawab A, Sharma N, Cottrill CL, Shapiro JI, Sodhi K. Phenotypic Alteration of Hepatocytes in Non-Alcoholic Fatty Liver Disease. Int J Med Sci 2018; 15(14):1591-1599. doi:10.7150/ijms.27953. Available from

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Non-Alcoholic Fatty Liver Disease (NAFLD) has been recognized as the most common liver disorder in developed countries. NAFLD progresses from fat accumulation in hepatocytes to steatohepatitis to further stages of fibrosis and cirrhosis. Simple steatosis, i.e. fat deposition in the liver, is considered benign and gives way to non-alcoholic steatohepatitis (NASH) with a higher probability of progressing to cirrhosis, and liver-related mortality. Evidence has been found that this progression has been associated with marked alterations in hepatocyte histology and a shift in marker expression of healthy hepatocytes including increased expression of peroxisome proliferator-activated receptor gamma (PPARγ), adipocyte protein (aP2), CD36, interleukin-6 (IL-6), interleukin-18 (IL-18) and adiponectin. This progression shares much in common with the obesity phenotype, which involves a transformation of adipocytes from small, healthy cells to large, dysfunctional ones that contribute to redox imbalance and the progression of metabolic syndrome. Further, activation of Src/ERK signaling via the sodium potassium adenosine triphosphatase (Na/K-ATPase) α-1 subunit in impaired hepatocytes may contribute to redox imbalance, exacerbating the progression of NAFLD. This review hypothesizes that an adipogenic transformation of hepatocytes propagates redox imbalance and that the processes occurring in adipogenesis become activated in fat-laden hepatocytes in liver, thereby driving progression to NAFLD. Further, this review discusses therapeutic interventions to reverse NAFLD including the thiazolidinediones (TZDs) and a variety of antioxidant species. The peptide, pNaKtide, which is an antagonist of Na/K-ATPase signaling, is also proposed as a potential pharmacologic option for reducing reactive oxygen species (ROS) and reversing NAFLD by inhibiting the Na/K-ATPase-modulated ROS amplification loop.

Keywords: Non-Alcoholic Fatty Liver Disease, Hepatocytes