Intersection of the unfolded protein response and hepatic lipid metabolism - PubMed (original) (raw)

Review

Intersection of the unfolded protein response and hepatic lipid metabolism

Ann-Hwee Lee et al. Cell Mol Life Sci. 2009 Sep.

Abstract

The liver plays a central role in whole-body lipid metabolism by governing the synthesis, oxidization, transport and excretion of lipids. The unfolded protein response (UPR) was identified as a signal transduction system that is activated by ER stress. Recent studies revealed a critical role of the UPR in hepatic lipid metabolism. The IRE1/XBP1 branch of the UPR is activated by high dietary carbohydrates and controls the expression of genes involved in fatty acid and cholesterol biosynthesis. PERK mediated eIF2alpha phosphorylation is also required for the expression of lipogenic genes and the development of hepatic steatosis, likely by activating C/EBP and PPARgamma transcription factors. Further studies to define the molecular pathways that lead to the activation of the UPR by nutritional cues in the liver, and their contribution to human metabolic disorders such as hepatic steatosis, atherosclerosis and type 2 diabetes that are associated with dysregulation of lipid homeostasis, are warranted.

PubMed Disclaimer

Figures

Fig. 1

Biochemical pathways leading to the synthesis of TAG and cholesterol. Glycolytic pathway generates Acetyl CoA from glucose imported into the cell through GLUT2. TAG and cholesterol are synthesized from Acetyl CoA by sequential enzymatic actions. GLUT2 Glucose transporter 2, GK glucokinase, L-PK liver pyruvate kinase, PEP phosphoenolpyruvate, ACC acetyl-CoA carboxylase, FASN fatty acid synthase, SCD stearoyl-CoA desaturase, GPAT glycerol-3-phosphate acyltransferase, DGAT diacylglycerol acyltransferase, HMG-CoA 3-hydroxy-3-methylglutaryl-coenzyme A, HMGCS HMG-CoA synthase, HMGCR HMG-CoA reductase

Fig. 2

Transcriptional control of hepatic lipogenesis. SREBP-2 is activated when cellular sterol levels are low, and controls the expression of genes involved in sterol biosynthesis. SREBP-1c and ChREBP are activated by insulin and glucose, respectively. Ingestion of carbohydrates increases circulating glucose and insulin levels, by inducing insulin production from pancreatic β cells. SREBP-1c and ChREBP bind to specific promoter elements to activate the transcription of genes in glycolytic and lipogenic pathways. XBP1 is required for the de novo synthesis of sterols and fatty acids in the liver and is activated in the presence of high glucose. The mechanism by which XBP1 controls sterol and fatty acid synthesis genes remains to be further investigated

Fig. 3

Overview of mammalian UPR signaling pathways. IRE1, PERK, and ATF6 are proximal ER stress sensors. IRE1, activated by autophosphorylation, removes 26 nucleotides from the XBP1 mRNA by using its cytosolic endoribonuclease activity. Spliced XBP1s protein is a potent transcription factor that induces diverse target genes. eIF2α phosphorylation by PERK impedes overall protein synthesis, while activating translation of some transcription factors. ATF4 plays a major role in PERK-dependent UPR target gene expression. ATF6 is a member of the family of ER transmembrane transcription factors, and normally resides in the ER associated with the ER chaperone BiP. Upon ER stress, ATF6 moves to the Golgi apparatus where site 1 (S1P) and site 2 proteases (S2P) sequentially cleave ATF6 to release the N-terminal part of the protein that translocates to the nucleus to activate its target genes

Fig. 4

Intersection of the UPR and hepatic lipid metabolism. a PERK/eIF2α and IRE1/XBP1 UPR signaling pathways control lipogenesis. eIF2α phosphorylation activates PPARγ and SREBP-1 in liver and mammary gland to increase the lipid synthesis. XBP1 activates the expression of the lipogenic genes, at least partly via direct interaction to target promoters. It is not fully understood what triggers UPR activation leading to increased lipogenesis. ER stress and high glucose may play a role. b Tunicamycin administration induces the ER stress and hepatic steatosis. Ironically, SREBP1 and lipogenic genes are downregulated by tunicamycin. Inhibition of ATF6α and eIF2α signaling pathways further increase fat accumulation, suggesting their protective roles in tunicamycin-induced steatosis. Tunicamycin induces degradation of ApoB protein, which is essential for VLDL secretion from the liver

Fig. 5

Transcriptional regulation of lipid synthesis in yeast. OPI1p is a critical repressor of lipid synthesis in yeast. It is anchored in the ER membrane through its interaction with Scs2p (reviewed in [185]). Inositol starvation activates INO2p–INO4p lipogenic transcription factors by preventing the release of OPI1p from the ER which antagonizes INO2p. Inositol starvation also activates the UPR. INO1 expression is impaired in IRE1 or HAC1 mutant yeasts, which display inositol auxotrophy. The mechanism by which the UPR contributes to the expression of lipogenic genes is not fully understood

References

1. Thurman RG, Kauffman FC, Jungermann K. Regulation of hepatic metabolism: intra- and intercellular compartmentation. New York: Plenum; 1986.
1. Horton JD, Goldstein JL, Brown MS. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J Clin Invest. 2002;109:1125–1131. - PMC - PubMed
1. Ferre P, Foufelle F. SREBP-1c transcription factor and lipid homeostasis: clinical perspective. Horm Res. 2007;68:72–82. - PubMed
1. Postic C, Dentin R, Denechaud PD, Girard J. ChREBP, a transcriptional regulator of glucose and lipid metabolism. Annu Rev Nutr. 2007;27:179–192. doi: 10.1146/annurev.nutr.27.061406.093618. - DOI - PubMed
1. Uyeda K, Repa JJ. Carbohydrate response element binding protein, ChREBP, a transcription factor coupling hepatic glucose utilization and lipid synthesis. Cell Metab. 2006;4:107–110. doi: 10.1016/j.cmet.2006.06.008. - DOI - PubMed

Intersection of the unfolded protein response and hepatic lipid metabolism - PubMed (original) (raw)