Molecular mechanisms of hepatic lipid accumulation in non-alcoholic fatty liver disease

Abstract

Non-alcoholic fatty liver disease (NAFLD) is currently the world's most common liver disease, estimated to affect up to one-fourth of the population. Hallmarked by hepatic steatosis, NAFLD is associated with a multitude of detrimental effects and increased mortality. This narrative review investigates the molecular mechanisms of hepatic steatosis in NAFLD, focusing on the four major pathways contributing to lipid homeostasis in the liver. Hepatic steatosis is a consequence of lipid acquisition exceeding lipid disposal, i.e., the uptake of fatty acids and de novo lipogenesis surpassing fatty acid oxidation and export. In NAFLD, hepatic uptake and de novo lipogenesis are increased, while a compensatory enhancement of fatty acid oxidation is insufficient in normalizing lipid levels and may even promote cellular damage and disease progression by inducing oxidative stress, especially with compromised mitochondrial function and increased oxidation in peroxisomes and cytochromes. While lipid export initially increases, it plateaus and may even decrease with disease progression, sustaining the accumulation of lipids. Fueled by lipo-apoptosis, hepatic steatosis leads to systemic metabolic disarray that adversely affects multiple organs, placing abnormal lipid metabolism associated with NAFLD in close relation to many of the current life-style-related diseases.

Keywords: Animal models; Lipid metabolism; Pharmacotherapy.

Fig. 1

Hepatic lipid acquisition and disposal. Intrahepatic lipid levels are governed by the balance between lipid acquisition and disposal constituting the four major pathways of hepatic lipid homeostasis. The liver acquires lipids through the uptake of circulating fatty acids and via de novo lipogenesis. Conversely, lipids may be disposed of through oxidation (in the mitochondria, peroxisomes and cytochromes) and through export as very low density lipoprotein (VLDL) particles. Consequently, lipid accumulation is the result of lipid acquisition pathways exceeding disposal pathways

Fig. 2

Overview of hepatic lipid metabolism. (1) Uptake of circulating lipids are facilitated by specific fatty acid transporters located in the hepatocyte plasma membrane and is regulated by PPARγ. FABP1 facilitates the transport of hydrophobic fatty acids to the different cellular compartments within the cytoplasm. (2) De novo lipogenesis converts acetyl-CoA (originating from excess carbohydrates) to new fatty acids, which subsequently can be esterified and stored as triglycerides. Regulation of de novo lipogenesis is complex, but broadly controlled by two key transcription factors: SREBP1c and ChREBP. (3) Fatty acid oxidation is controlled by PPARα and reduces intrahepatic fat levels by utilizing lipids as an energy source. While the process primarily occurs in the mitochondria, lipid overload and/or compromised mitochondrial function forces a higher degree of fatty acid oxidation to take place in the peroxisomes and cytochromes, thereby, generating ROS. (4) The liver can export lipids by packaging them into water-soluble VLDL-particles, which may then be utilized or stored in other tissues. ChREBP carbohydrate regulatory element binding protein, CPT carnitine palmitoyltransferase, FABP fatty acid binding protein, PPAR peroxisome proliferator-activated receptor, ROS reactive oxygen species, SREBP1c sterol regulatory element binding protein 1c, VLDL very low density lipoprotein

Fig. 3

Effects on hepatic lipid metabolism in NAFLD. While the role of hepatic caveolins is still unclear, CD36, FATP2 and -5 mediates increased uptake of circulating lipids in NAFLD. Initially, FABP1 is increased, but levels may decline with disease progression, potentially limiting the mobility of fatty acids and sustaining steatosis. Enhanced SREBP1c-mediated de novo lipogenesis is a key feature of NAFLD contributing significantly to the accumulation of lipids. At the same time, ChREBP which could be hepatoprotective, appears to be downregulated in NAFLD. Although data relating to the regulation of fatty acid oxidation are conflicting, mitochondrial dysfunction is an important feature of NAFLD resulting in increased generation of ROS and utilization of cytochrome- and peroxisome-mediated oxidation. This further promotes oxidative stress, in turn inducing damage to the mitochondrial membranes, compromising cellular respiration and metabolism, and impairing liver function by direct and indirect cellular damage. Lastly, lipid export increases with hepatic triglyceride levels. However, in the setting of NASH, levels of MTTP and apoB100 may be decreased, hereby, limiting VLDL export and instead facilitating lipid accumulation. The net result is an escalating vicious circle, driven by chronic dyslipidemia and hepatic lipid overload, leading to detrimental consequences for liver metabolism and function and ultimately promoting irreversible liver damage. Green arrow: increased expression. Red arrow: decreased expression. Purple arrow: expression different between steatosis and NASH. ACC acetyl-CoA carboxylase, ApoB100 apolipoprotein B100, CD36 cluster of differentiation 36, ChREBP carbohydrate regulatory element binding protein, ELOVL elongation of very long chain fatty acid, FABP fatty acid binding protein, FASN fatty acid synthase, FATP fatty acid transport protein, MTTP microsomal triglyceride transfer protein, PPAR peroxisome proliferator-activated receptor, ROS reactive oxygen species, SCD1 stearoyl-CoA desaturase 1, SREBP1c sterol regulatory element binding protein 1c, VLDL very low density lipoprotein