Molecular mechanisms and the role of saturated fatty acids in the progression of non-alcoholic fatty liver disease

Abstract

The steady rise in Western obesity rates has been closely linked to significant increases in a multitude of accompanying health problems including non-alcoholic fatty liver disease (NAFLD). NAFLD severity ranges from simple steatosis to acute steatohepatitis, but the molecular mechanisms controlling progression of this disease are poorly understood. Recent literature suggests that elevated free fatty acids (FFAs), especially saturated FFAs, may play an important role in lipotoxic mechanisms, both in experimental models and in NAFLD patients. This review highlights important cellular pathways involved in hepatic lipotoxicity and how the degree of intrahepatic lipid saturation controls cell fate in response to an elevated FFA load. Relevant cellular processes that have been causally linked to lipid-induced apoptosis, known as lipoapoptosis, include endoplasmic reticulum (ER) stress, oxidative stress, mitochondrial dysfunction, and Jun N-terminal kinase (JNK) signaling. In contrast, increased triglyceride synthesis has been shown to have a protective effect against lipotoxicity, despite being one of the hallmark traits of NAFLD. Developing a more nuanced understanding of the molecular mechanisms underlying NAFLD progression will lead to more targeted and effective therapeutics for this increasingly prevalent disease, which to date has no proven pharmacologic treatment to prevent or reverse its course.

Figure 1. Saturated fatty acids initiate cellular dysfunction in lipotoxicity/NAFLD

Lipolysis of subcutaneous and visceral adipose tissue gives rise to higher concentrations of free fatty acids in the blood resulting in ectopic fat storage within the liver. Upon entering the liver, FFAs are partitioned toward three main lipid disposal pathways: β-oxidation, TG synthesis, and phospholipid synthesis/remodeling. Mitochondrial β-oxidation gradually breaks down fatty acids into two-carbon acetyl-CoA units, which are subsequently used to fuel the TCA cycle. Esterification of FFAs into TG and phospholipids provides an alternate route for disposing of elevated FFAs. High concentrations of saturated fatty acids, however, avoid protective sequestration into triglyceride stores and/or β-oxidation. Instead, SFAs are channeled toward phospholipid incorporation. Increased saturation of ER phospholipids can compromise the integrity of the ER-membrane structure resulting in stimulation of UPR signaling pathways and disruption of mitochondrial function. Additionally, elevated SFAs deregulate TCA cycle metabolism leading to ROS accumulation. Both ER-stress pathways and mitochondrial dysfunction activate JNK stress signaling, thus leading to eventual apoptotic cell death. Abbreviations: Monounsaturated fatty acid (MUFA); Endoplasmic reticulum (ER); Protein kinase RNA-like endoplasmic reticulum kinase (PERK); Inositol-requiring protein–1 (IRE-1); Xbox binding protein-1 spliced (XBS-1s); Activating transcription factor 6 (ATF-6); Jun N-terminal kinase (JNK); Reactive oxygen species (ROS).