Phenotypic Alteration of Hepatocytes in Non-Alcoholic Fatty Liver Disease

Abstract

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.

Emergent Properties of the HNF4α-PPARγ Network May Drive Consequent Phenotypic Plasticity in NAFLD

“…This process can be viewed as "trans-differentiation" of the cell, i.e., conversion of hepatocytes to hybrid adipocyte-like cell state by simultaneous repression of the original tissue (liver) homeostatic mechanisms and activation of a different tissue-specific (adipose tissue) program. This result is consistent with observations of multiple adipocytic markers reported in histological samples of NAFLD patients [60]. In the liver, such trans-differentiation has also been from the HL (hepatocyte; HNF4α high-PPARγ low) state to the HH state (hybrid; HNF4α high-PPARγ high) and vice versa ( Figure 4C).…”

“…This core regulatory network is also capable of existing in a "hybrid" state, an adipocyte-like phenotype of the hepatocytes, which might correspond to observations during the progression of NAFLD. This "hybrid" state can be mapped on the presence of large lipid droplets in the hepatocytes with an increased expression of adipocytic markers and enhanced release of various pro-inflammatory cytokines such as IL-6, IL-18, and TNFα, both of which are hallmark features of adipocytes [60]. Our mathematical model also predicts that the hepatocytes can spontaneously switch to form the "hybrid" state under the influence of biological noise.…”

Emergent properties of HNF4α-PPARγ network may drive consequent phenotypic plasticity in NAFLD

“…conversion of hepatocytes to hybrid adipocyte-like cell state by simultaneous repression of the original tissue (liver) homeostatic mechanisms and activation of a different tissue-specific (adipose tissue) program. This result is consistent with observations of multiple adipocytic markers reported in histological samples of NAFLD patients [53]. In the liver, such trans-differentiation has also been observed for quiescent hepatic stellate cells that can attain adipogenic or myogenic characteristics depending on the relative abundance of adipogenic or myogenic genes respectively [54].…”

“…This core regulatory network is also capable of existing in a "hybrid" state, adipocyte like phenotype of the hepatocytes, which might correspond to observations during the progression of NAFLD. This "hybrid" state is characterized by the presence of large lipid droplets in the hepatocytes with an increased expression of adipocytic makers and enhanced release of various proinflammatory cytokines such as IL-6, IL-18 and TNFα, both of which are hallmark features of adipocytes [53]. We also showed that the hepatocytes can spontaneously switch to form the "hybrid" state under the influence of biological noise.…”

MiR-455 targeting SOCS3 improve liver lipid disorders in diabetic mice

“…Liver is a central regulator of lipid metabolism in human [26]. Nowadays, a lot of researches have already confirmed that plenty of molecules are involved in the lipid metabolism, including PPARγ, SREBP-1c, FAS and ACCα [26][27][28]. As the crucial genes for the development of NAFLD, these genes were significantly up-regulated in the liver of db/db mice.…”