Free radical biology for medicine: learning from nonalcoholic fatty liver disease

Abstract

Reactive oxygen species, when released under controlled conditions and limited amounts, contribute to cellular proliferation, senescence, and survival by acting as signaling intermediates. In past decades there has been an epidemic diffusion of nonalcoholic fatty liver disease (NAFLD) that represents the result of the impairment of lipid metabolism, redox imbalance, and insulin resistance in the liver. To date, most studies and reviews have been focused on the molecular mechanisms by which fatty liver progresses to steatohepatitis, but the processes leading toward the development of hepatic steatosis in NAFLD are not fully understood yet. Several nuclear receptors, such as peroxisome proliferator-activated receptors (PPARs) α/γ/δ, PPARγ coactivators 1α and 1β, sterol-regulatory element-binding proteins, AMP-activated protein kinase, liver-X-receptors, and farnesoid-X-receptor, play key roles in the regulation of lipid homeostasis during the pathogenesis of NAFLD. These nuclear receptors may act as redox sensors and may modulate various metabolic pathways in response to specific molecules that act as ligands. It is conceivable that a redox-dependent modulation of lipid metabolism, nuclear receptor-mediated, could cause the development of hepatic steatosis and insulin resistance. Thus, this network may represent a potential therapeutic target for the treatment and prevention of hepatic steatosis and its progression to steatohepatitis. This review summarizes the redox-dependent factors that contribute to metabolism alterations in fatty liver with a focus on the redox control of nuclear receptors in normal liver as well as in NAFLD.

Keywords: 3-hydroxy-3-methylglutaryl-CoA reductase; 4-HNE; 4-hydroxynonenal; ACC; ACOX; ALA; AMP-activated protein kinase; AMPK; CAT; CPT-1; CREB; ER; FA; FA translocase; FAS; FAT/CD36; FOX; FXR; Free radicals; G-3-P; GPX; GRx; GSH; GST; HC; HMG-CoAR; Hepatic steatosis; IRS; LXR; MAPK; MCD; NAFLD; NASH; NFE2L2; NR; NRF; Nuclear receptors; PGC-1α/β; PPARα/γ/δ; PPARγ coactivators 1α and 1β; ROS; Redox signaling; SCD1; SOD; SREBP; TAG; TCA; UCP-2; UPR; acetyl-CoA carboxylase; acyl-CoA oxidase; cAMP-responsive element-binding protein; carnitine palmitoyl transferase 1; catalase; endoplasmic reticulum; farnesoid-X-receptor; fatty acid; fatty acid synthase; forkhead box class; glutathione; glutathione S-transferase; glutathione peroxidase; glutathione reductase; glycerol 3-phosphate; hydroxycholesterol; insulin receptor substrate; liver-X-receptor; malonyl-CoA decarboxylase; mitochondrial transcription factor A; mitogen-activated protein kinase; mtTFA; nonalcoholic fatty liver disease; nonalcoholic steatohepatitis; nuclear factor (erythroid-derived 2)-like 2; nuclear receptor; nuclear respiratory factor; peroxisome proliferator-activated receptors α/γ/δ; reactive oxygen species; stearoyl-CoA desaturase-1; sterol-regulatory element-binding protein; superoxide dismutase; triacylglycerol; tricarboxylic acid; uncoupling protein 2; unfolded protein response; α-lipoic acid.