Nuclear Receptors in Nonalcoholic Fatty Liver Disease

Figure 2

NRs as central regulators of hepatic lipid metabolism. Oxysterols activate the LXR, whereas bile acids (BA) stimulate SHP expression through the FXR (not shown). The LXR activates SREBP-1c and induces de novo fatty acid (FA) synthesis and hypertriglyceridemia by activating FAS, ACC, SCD1, and ChREBP (a glucose-sensitive transcription factor that promotes the hepatic conversion of carbohydrates into lipids). Several important proteins that could mediate the LXR-mediated hypertriglyceridemic effect are regulated. One protein is angiopoietin-like protein 3 (Angptl3), a liver-secreted protein that increases both plasma triglyceride level by inhibiting LPL activity in different tissues and free fatty acid level by activating lipolysis in adipocytes. LXR activation increases the expression of Angptl3 and LPL and downregulates apoA-V expression. Activation of the FXR leads to the repression of hepatic lipogenesis by reducing the expression of SREBP-1c. By increasing the expression of PPARα, the FXR also promotes FFA catabolism via β-oxidation, which induces ACO-OX, ACS, ECA, HMG-CoAS, FAB1, and FATP. By repressing the expression of MTP, an enzyme that controls VLDL assembly, the FXR reduces VLDL production. Activation of the FXR increases TG clearance by promoting LPL activity, via induction of ApoC-II and B1R. Activation of the FXR also reduces TG clearance by decreasing the expression of ApoC-III and Angptl3, two LPL inhibitors. PPARα can be activated by FXR and fibrates (not shown). PPAR activation leads to β-oxidation, which induces ACO-Ox, ACS, ECA, HMG-CoAS, FAB1, and FATP. Others genes are regulated. For example, LPL, which is involved in the degradation of TG, is activated, and APOA1 and APOCIII are both downregulated. The activation pathways are shown by green arrows, inhibitory pathways by red lines, and inhibited activation pathways by broken green arrows. Angptl3: angiopoietin-like protein 3; ACC: acetyl-CoA carboxylase; Apo: apolipoprotein; ChREBP: carbohydrate response element-binding protein; FAS: fatty acid synthase; FATP: fatty acid transport protein; FXR: farnesoid X receptor; LPL: lipoprotein lipase; LXR: liver X receptor; MTP: microsomal triglyceride transfer protein; PPAR: peroxisome proliferator-activated receptor; SCD1: stearoyl-coenzyme A desaturase 1; SREBP-1c: sterol regulatory element-binding protein-1c; TG: triglyceride. Arrows and stop bars indicate positive regulation or activation and negative regulation or repression, respectively.