Cellular heterogeneity and plasticity during NAFLD progression

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a progressive liver disease that can progress to nonalcoholic steatohepatitis (NASH), NASH-related cirrhosis, and hepatocellular carcinoma (HCC). NAFLD ranges from simple steatosis (or nonalcoholic fatty liver [NAFL]) to NASH as a progressive form of NAFL, which is characterized by steatosis, lobular inflammation, and hepatocellular ballooning with or without fibrosis. Because of the complex pathophysiological mechanism and the heterogeneity of NAFLD, including its wide spectrum of clinical and histological characteristics, no specific therapeutic drugs have been approved for NAFLD. The heterogeneity of NAFLD is closely associated with cellular plasticity, which describes the ability of cells to acquire new identities or change their phenotypes in response to environmental stimuli. The liver consists of parenchymal cells including hepatocytes and cholangiocytes and nonparenchymal cells including Kupffer cells, hepatic stellate cells, and endothelial cells, all of which have specialized functions. This heterogeneous cell population has cellular plasticity to adapt to environmental changes. During NAFLD progression, these cells can exert diverse and complex responses at multiple levels following exposure to a variety of stimuli, including fatty acids, inflammation, and oxidative stress. Therefore, this review provides insights into NAFLD heterogeneity by addressing the cellular plasticity and metabolic adaptation of hepatocytes, cholangiocytes, hepatic stellate cells, and Kupffer cells during NAFLD progression.

Many Faces of Regulatory T Cells: Heterogeneity or Plasticity?

“… No genetic alterations occur. [ 16 , 17 , 20 ] Once initiated during the developmental process, becomes fixed and remains stable under physiological conditions. Unstable and reversible.…”

Bariatric-Metabolic Surgery: A Promising Solution for Non-Alcoholic Steatohepatitis

“…[8][9][10] Factors contributing to this heterogeneity include genetic predisposition, metabolic factors, lifestyle and comorbidities. 3,[11][12][13] This makes it challenging to develop a one-size-fits-all treatment approach and highlights the need for personalized, tailored treatment strategies. The pathogenesis of NASH involves multiple interrelated mechanisms, including insulin resistance, lipid metabolism dysfunction, oxidative stress, inflammation and fibrosis.…”

Cell-type specific role of autophagy in the liver and its implications in non-alcoholic fatty liver disease

“…Furthermore, the prevalence of NAFLD, which is currently > 30%, has increased significantly in the last ten years with a nearly 50% increase occurring between 1990-2006 to 2016-2019[ 2 ]. At the molecular level, the development of NAFLD involves pathological changes in several hepatic cells including hepatocytes, macrophages, hepatic stellate cells (HSCs), endothelial cells and cholangiocytes[ 9 ]. Intracellular changes in the cellular metabolism, mitochondrial energetics, organellar homeostasis, redox hormesis and epigenetic changes in cellular plasticity govern the tissue damage and inflammatory milieu observed during NAFLD progression[ 10 - 13 ].…”