Nonalcoholic Fatty Liver Disease: Pathogenesis and Therapeutics from a Mitochondria-Centric Perspective

Abstract

Nonalcoholic fatty liver disease (NAFLD) describes a spectrum of disorders characterized by the accumulation of triglycerides within the liver. The global prevalence of NAFLD has been increasing as the obesity epidemic shows no sign of relenting. Mitochondria play a central role in hepatic lipid metabolism and also are affected by upstream signaling pathways involved in hepatic metabolism. This review will focus on the role of mitochondria in the pathophysiology of NAFLD and touch on some of the therapeutic approaches targeting mitochondria as well as metabolically important signaling pathways. Mitochondria are able to adapt to lipid accumulation in hepatocytes by increasing rates of beta-oxidation; however increased substrate delivery to the mitochondrial electron transport chain (ETC) leads to increased reactive oxygen species (ROS) production and eventually ETC dysfunction. Decreased ETC function combined with increased rates of fatty acid beta-oxidation leads to the accumulation of incomplete products of beta-oxidation, which combined with increased levels of ROS contribute to insulin resistance. Several related signaling pathways, nuclear receptors, and transcription factors also regulate hepatic lipid metabolism, many of which are redox sensitive and regulated by ROS.

Analysis of Molecular Mechanisms of 5-Fluorouracil Induced Steatosis and Inflammation in Vitro and in Mice

“…Together, impaired mitochondrial and enhanced peroxisomal fatty acid metabolism lead to oxidative stress. www.impactjournals.com/oncotarget ROS are known inducers of pro-inflammatory genes [30,31], and indeed we observed increased IL-8 and ICAM-1 expression as well as induced hepatic infiltration with immune cells in response to 5-FU treatment. Moreover, 5-FU treatment led to a significant activation of JNK.…”

“…The 5-FUinduced ACOX1 expression continued to increase beyond the observed time period of 24 h ( Figure 2E) and resulted in approximately 4-fold higher expression levels after 24 h stimulation ( Figure 2F). Peroxisomal β-oxidation is known to lead to the production of reactive oxygen species (ROS) [27,[30][31][32], and the antioxidant enzyme heme oxygenase 1 (HMOX1) has been shown to be increased in response to oxidative stress [33]. Stimulation with 5-FU caused a time-and dose-dependent induction of HMOX1 expression levels ( Figure 2G, 2H) that paralleled the pattern of 5-FU effects on ACOX1 mRNA levels.…”

Az idült májbetegségek progressziójához vezető folyamatok

“…A mitokondriális ROS-termelődés szerepet játszik az inzulinrezisztencia kialakulásában és az elektrontranszportlánc működésének csökkenésében. A csökkent működésű mitokondriumokban így felborul a β-oxidáció és az oxidatív foszforiláció egyensúlya, amely részlegesen oxidált közti termékek felhalmozódásához vezet, amelyek tovább rontják a folyamatot [24].…”

“…A ROS károsítja az elektrontranszportlánc-(ETC-) komplexeket, és a mitokondriális DNS-ben mutációkat hoz létre. Emellett reaktívnitrogén-gyökök (RNS) is károsítják a légzési lán-cot [24,32].…”

Treating fatty liver disease by modulating mitochondrial pyruvate metabolism

“…At its core, NAFLD is caused by fat accumulation that is likely driven by nutrient excess. At the same time, the progression to NASH in mice and humans has been tightly linked to a number of factors, including insulin resistance,14, 15 abnormal mitochondrial function,16, 17, 18, 19 oxidative damage, and hepatic inflammation, that promote a state conducive to necropoptosis and replacement of dead hepatocytes with a collagen matrix secreted by hepatic stellate cells in response to these stimuli 20, 21. It is interesting to note that the entire spectrum of this pathophysiology from insulin resistance to fibrotic scarring may involve dysfunctional metabolism driven by overnutrition.…”