Non-alcoholic fatty liver disease and lipotoxicity

Abstract

Non-alcoholic fatty liver disease (NAFLD) has become the most common liver pathology worldwide due to the rising prevalence of obesity. This term includes changes from simple steatosis to steatohepatitis and fibrosis. It was previously thought to be a hepatic manifestation of metabolic syndrome, but recent literature describes this relation as much more complex and bi-directional. Development of NAFLD is associated with other metabolic syndrome components but it can also exacerbate insulin resistance and increase cardiovascular risk. Recently a lot of attention is brought to the role of lipids and lipotoxicity in pathogenesis and progression of non-alcoholic fatty disease. It seems that some lipid classes can be protective against liver injury while others are harmful in excessive amounts. This study presents an overview of the main lipids involved in the pathogenesis of non-alcoholic fatty liver disease and summarizes their association with lipotoxicity, insulin resistance, oxidative stress and other processes responsible for its progression.

ULK1 Signaling in the Liver: Autophagy Dependent and Independent Actions

“…Lipotoxicity is a term used to define tissue damage originating from the excessive accumulation of lipid species in the nonadipose tissues such as liver, pancreas, muscle and heart (Wasilewska and Lebensztejn, 2021). Lipotoxicity in the liver is associated with NAFLD, wherein excessive lipid accumulation drives liver inflammation, hepatocyte death, and fibrosis (Wasilewska and Lebensztejn, 2021).…”

Inflammation and Fibrogenesis in MAFLD: Role of the Hepatic Immune System

“…The typical alterations observed in NAFLD patients (high triglycerides, FFAs, and insulin) led to the hypothesis that it could be a condition characterized by metabolic inflexibility ( 8 ). A key element for the pathogenesis of NAFLD is the excess of fat and lipotoxicity ( 51 , 63 , 64 ). The latter, rather than the excess of fat alone, is associated with disease progression ( 65 ).…”

“…The excess of circulating FFAs and the consequent abnormal liver uptake and fat accumulation typical of NAFLD, derives from abnormal lipolysis (hydrolysis of triglyceride) in the adipose tissue, mediated by insulin resistance, which is the event responsible for the largest share of hepatic fat accumulation, increased de novo lipogenesis (starting from glucose or fructose), and excess in dietary fat intake ( 64 , 66 , 67 ). Fatty acids in the liver are addressed to oxidation (mitochondrial β-oxidation, or oxidation in peroxisomes, or microsomes) or are esterified to triglycerides (TGs), to form very low-density lipoprotein (VLDL) particles, which will be secreted, or lipid droplets, which will be stored in the hepatocytes ( 63 , 64 , 67 ). Triglycerides formation, although associated with steatosis, is thought to be a protective response to an excess of fats, as it will be stored in an inert, non-toxic form ( 50 , 63 , 67 , 68 ).…”

“…Fatty acids in the liver are addressed to oxidation (mitochondrial β-oxidation, or oxidation in peroxisomes, or microsomes) or are esterified to triglycerides (TGs), to form very low-density lipoprotein (VLDL) particles, which will be secreted, or lipid droplets, which will be stored in the hepatocytes ( 63 , 64 , 67 ). Triglycerides formation, although associated with steatosis, is thought to be a protective response to an excess of fats, as it will be stored in an inert, non-toxic form ( 50 , 63 , 67 , 68 ). Saturation of the processes responsible FFAs handling, due to the large amount that reaches the hepatic parenchyma, leads to alterations in mitochondrial function and an increase in the production of reactive oxygen species (ROS) ( 69 ).…”

Cell Models and Omics Techniques for the Study of Nonalcoholic Fatty Liver Disease: Focusing on Stem Cell-Derived Cell Models

“…Moreover, with marked lipid metabolism dysregulation, which occurs in NAFLD, mitochondrial β-oxidation is insufficient to metabolize excess NEFAs, which accumulate in hepatocytes and may lead to more lipotoxic species forming (e.g., ceramides, diacylglycerols, lysophosphatidylcholines, or other lysophosphatidic acid derivatives, saturated fatty acids, and oxidized low-density lipoproteins) [ 20 , 30 , 31 ]. This excessive accumulation of fat and lipotoxic intermediates has deleterious effects on diverse cell organelles and functions, which are generally known as lipotoxicity ( Figure 1 ).…”