Molecular pathways in non-alcoholic fatty liver disease

Abstract

Non-alcoholic fatty liver disease (NAFLD) is a clinicopathological change characterized by the accumulation of triglycerides in hepatocytes and has frequently been associated with obesity, type 2 diabetes mellitus, hyperlipidemia, and insulin resistance. It is an increasingly recognized condition that has become the most common liver disorder in developed countries, affecting over one-third of the population and is associated with increased cardiovascular- and liver-related mortality. NAFLD is a spectrum of disorders, beginning as simple steatosis. In about 15% of all NAFLD cases, simple steatosis can evolve into non-alcoholic steatohepatitis, a medley of inflammation, hepatocellular injury, and fibrosis, often resulting in cirrhosis and even hepatocellular cancer. However, the molecular mechanism underlying NAFLD progression is not completely understood. Its pathogenesis has often been interpreted by the “double-hit” hypothesis. The primary insult or the “first hit” includes lipid accumulation in the liver, followed by a “second hit” in which proinflammatory mediators induce inflammation, hepatocellular injury, and fibrosis. Nowadays, a more complex model suggests that fatty acids (FAs) and their metabolites may be the true lipotoxic agents that contribute to NAFLD progression; a multiple parallel hits hypothesis has also been suggested. In NAFLD patients, insulin resistance leads to hepatic steatosis via multiple mechanisms. Despite the excess hepatic accumulation of FAs in NAFLD, it has been described that not only de novo FA synthesis is increased, but FAs are also taken up from the serum. Furthermore, a decrease in mitochondrial FA oxidation and secretion of very-low-density lipoproteins has been reported. This review discusses the molecular mechanisms that underlie the pathophysiological changes of hepatic lipid metabolism that contribute to NAFLD.

Carnitine transport and fatty acid oxidation

“…2) [3]. The main proteins involved in the transfer of fatty acids across the plasma membrane are: fatty acid transport proteins (FATPs), fatty acid translocase (FAT/CD36), caveolins, and plasma membrane fatty acid binding proteins (FABPpm) [18–20]. …”

“…FAT/CD36 ( CD36 gene) is expressed in a wide variety of cells including macrophages, adipocytes, myocytes, enterocytes, and hepatocytes and functions as a receptor for collagen, thrombospondin, Plasmodium falciparum infected red blood cells [37], apoptotic neutrophils, oxidized low density lipoproteins, and as a transporter for long chain fatty acids [18]. This transmembrane protein facilitates the uptake and intracellular trafficking of free fatty acids, as well as esterification into triglycerides in heart and skeletal muscle cells [2, 18, 38, 39].…”

IL-17 Axis Driven Inflammation in Non-Alcoholic Fatty Liver Disease Progression

“…Specifically, increased release of free fatty acids by white adipose tissue is responsible for augmented triglyceride synthesis and storage in hepatocytes (NAFL)–something that represents the “first hit” in NAFLD, and renders hepatocytes susceptible to stress mediated damage [101]. This obesity-associated lipotoxicity is inflammatory in nature and further renders the hepatocytes susceptible to parallel/sequential hits, potential cell death, and disease progression [101]. Of note, IL-17A stimulation is known to increase hepatocyte lipid uptake and hepatocyte-driven cytokine production [83].…”

Omega-3 polyunsaturated fatty acids in treating non-alcoholic steatohepatitis: A randomized, double-blind, placebo-controlled trial

“…Mechanisms driving the transition from simple steatosis to NASH and the later degrees of NAFLD are multifactorial and seem to involve oxidative stress, lipotoxicity, insulin resistance, and central inflammatory signalling pathways [2,3]. Maintaining a proper body weight and a healthy lifestyle seem to provide benefits for controlling NASH development [4].…”