Nonalcoholic Fatty liver disease: pathogenesis and therapeutics from a mitochondria-centric perspective

Aaron M Gusdon, Ke-Xiu Song, Shen Qu, Aaron M Gusdon, Ke-Xiu Song, Shen Qu

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.

Figures

Figure 1
Figure 1
Pathways involved in the development of NAFLD. The role of mitochondria is highlighted as increased reactive oxygen species (ROS) production leads to inactivation of the ETC resulting in decreased ATP levels and impaired energy supply. Mitochondrial damage by ROS also leads to impaired fatty acid oxidation (FAO). Incomplete FAO may also occur as a result of ROS production and contribute to insulin resistance and further hepatic fatty acid accumulation. ROS production also leads to the activation of a number of cytokines known to play a role in the pathogenesis of NAFLD. Insulin signaling plays a key role in NAFLD. Insulin signals through SREP-1c, which activates lipogenesis. In states of insulin resistance, this ability to stimulate lipogenesis is maintained while the ability to stimulate glucose uptake is reduced. Glucose stimulates lipogenesis as well but does so by activating ChREBP. LXR/FXR and RXR also play key roles in increasing lipogenesis. Signaling through AMPK decreases lipogenesis by inhibiting ACC. However, AMPK also has very broad effects on the cellular energy state leading to decreased levels of ATP and subsequent activation of pyruvate kinase, phosphofructokinase, and pyruvate dehydrogenase. The PPAR family of transcription factors plays an important role in lipid metabolism with PPARα stimulating fatty acid oxidation and PPARγ increasing peripheral update of lipid by adipocytes. PGC-1α is a transcription factor which can lead to activation of gluconeogenesis when activated by CREB or ROS production. However PGC-1α also leads to increased mitochondrial biogenesis when activated by AMPK or metformin which may ameliorate NAFLD.

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