Abstract
Lipids play Jekyll and Hyde in the liver. On the one hand, the lipid-laden status of hepatic stellate cells is a hallmark of healthy liver. On the other hand, the opposite is true for lipid-laden hepatocytes—they obstruct liver function. Neglected lipid accumulation in hepatocytes can progress into hepatic fibrosis, a condition induced by the activation of stellate cells. In their resting state, these cells store substantial quantities of fat-soluble vitamin A (retinyl esters) in large lipid droplets. During activation, these lipid organelles are gradually degraded. Hence, treatment of fatty liver disease is treading a tightrope—unsophisticated targeting of hepatic lipid accumulation might trigger problematic side effects on stellate cells. Therefore, it is of great importance to gain more insight into the highly dynamic lipid metabolism of hepatocytes and stellate cells in both quiescent and activated states. In this review, part of the special issue entitled “Cellular and Molecular Mechanisms underlying the Pathogenesis of Hepatic Fibrosis 2020”, we discuss current and highly versatile aspects of neutral lipid metabolism in the pathogenesis of non-alcoholic fatty liver disease (NAFLD).
Highlights
Chronic liver diseases affect hundreds of millions of people worldwide
Non-alcoholic fatty liver disease (NAFLD) represents a wide range of liver diseases that are all caused by stimuli other than excessive alcohol consumption, covering simple steatosis, non-alcoholic steatohepatitis (NASH), fibrosis and its more severe form cirrhosis
Simplified cartoons of healthy liver with normal hepatocytes flanked by a quiescent hepatic stellate cell (HSC) with large lipid droplets (LDs), and injured liver with lipid-filled hepatocytes flanked by activated hepatic stellate cells (HSCs) devoid of large LDs
Summary
Chronic liver diseases affect hundreds of millions of people worldwide. Non-alcoholic fatty liver disease (NAFLD) represents a wide range of liver diseases that are all caused by stimuli other than excessive alcohol consumption, covering simple steatosis (the accumulation of fat in hepatocytes), non-alcoholic steatohepatitis (NASH), fibrosis and its more severe form cirrhosis. Liver-resident HSCs are specialized in the storage of vitamin A as REs, a fat-soluble vitamin required for, e.g., vision, development, and reproduction. These cells are important players in NAFLD and will be discussed in more detail later in this review. Hepatocytes store limited amounts of neutral lipids in LDs. In contrast, HSCs contain large LDs, responsible for the storage of most of the vitamin A in the body [17,21]. Strategies to keep HSCs in an LD-rich state and at the same time lower LDs in hepatocytes are likely to be instrumental in the prevention or reversal of liver fibrosis. We end with discussing recent promising models to better study the mechanisms of liver disease and screen for potential therapeutic drugs in vitro
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