Nuclear Receptors in Nonalcoholic Fatty Liver Disease

Figure 3

Activation of the PXR induces lipogenesis and inhibits fatty acid β-oxidation. The PXR induces lipogenesis through activation of CD36, PPARγ, SCD1, and FAE gene expression. The PXR inhibits fatty acid β-oxidation through its suppression of PPARα and thiolase gene expression. In addition, PXR binds to FoxA2, a key regulator of β-oxidation, and inhibits FoxA1-mediated activation of Cpt1a and Hmgcs2 gene expression. CAR activation inhibits lipogenesis by inducing Insig-1, a protein that plays a role in SREBP-mediated regulation of lipogenic genes. Insig proteins bind and trap SCAP, retaining it in the ER and preventing it from escorting SREBPs to the site of proteolytic activation in the Golgi complex (not shown). SREBPs are cleaved by two proteases in the Golgi complex, and the bHLH-Zip domain of SREBPs transfers from the membrane to the nucleus to bind the sterol response elements in the promoter region of the target genes (not shown). CAR inhibits fatty acid β-oxidation. CAR competes with PPARα for its binding site in the 3-hydroxyacyl CoA dehydrogenase gene promoter. Activation of CAR also decreases the expression of Cpt1, a rate-limiting enzyme of β-oxidation. Arrows and stop bars indicate positive regulation or activation and negative regulation or repression, respectively. Cpt1a: carnitine palmitoyltransferase 1a; FAE: long-chain free fatty acid elongase; FoxA2: forkhead box factor A2; Hmgcs2: mitochondrial 3-hydroxy-3-methylglutaryl CoA synthase 2; PPAR: peroxisome proliferator-activated receptor; SCAP: SREBP cleavage-activating protein; SCD1: stearoyl CoA desaturase 1; SREBP: sterol regulatory-element binding protein.