Nuclear Receptors in Nonalcoholic Fatty Liver Disease

Table 1

Nuclear receptors in hepatic lipid metabolism.

RXR partner	Ligands	Official name	Role in hepatic lipid metabolism
LXR𝛼	Oxysterols (22(R)-hydroxycholesterol, 24(S)-hydroxycholesterol, 24(S),25-epoxycholesterol, 27-hydroxycholesterol) and fatty acids	NR1H3	(i) Increases fatty acid synthesis, TG level, HDL level, cholesterol secretion
			(ii) Upregulation of SREBP-c^𝐹𝐴𝑆𝐴𝐶𝐶𝑆𝐶𝐷1
			(iii) Upregulation of ChREBP, Angptl3
			(iv) Downregulation of ApoA-V
PPAR𝛼	Fatty acids, fibrates, statins, eicosanoids, and leukotrienes	NR1C1	(i) Promotes fatty acid oxidation (by lipoprotein lipase activation)
			(ii) Improves insulin resistance
			(iii) Suppression: acyl CoA oxidase (ACO-OX), acyl CoA synthase (ACS), enoyl-CoA hydratase, malic enzyme, HMG-CoA synthase, mitochondrial enzymes, APOA1 and APOCIII
FXR	Bile acids, pregnadiene, and fexaramine	NR1H4	(i) Induces lipoprotein metabolism genes/clearance represses hepatic genes involved in the synthesis of TG
			(ii) Induces human PPAR𝛼
			(iii) Increases hepatic expression of receptors VLDL
			(iv) Reduces: hepatic lipogenesis and plasma triglyceride and cholesterol levels
			(v) Decreases expression of proteins apoC-III and Angptl3 (inhibitors of LPL)
PXR	Pregnanes, progesterone, and glucocorticoids, LCA, xenobiotics/drugs, rifampicin	NR1I2	(i) Induces lipogenesis by increasing expression of the fatty acid translocase CD36, SCD-1, and long-chain free fatty acid elongase
			(ii) Suppression of several genes involved in fatty acid 𝛽-oxidation (PPAR𝛼, thiolase, carnitine palmitoyltransferase 1a (Cpt1a), and mitochondrial 3-hydroxy-3-methylglutaryl CoA synthase 2 (Hmgcs2))
CAR	Androstane metabolites, estrogens, progesterone, and xenobiotics	NR1I3	(i) Induction of Insig-1, a protein with antilipogenic
			properties
			(ii) Interacts with PPAR𝛼 during fasting
			(iii) Suppresses lipid metabolism and lowers serum triglyceride level by reducing SREBP-1 level