Intersection of the unfolded protein response and hepatic lipid metabolism.
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.
Lee
Ann-Hwee
AH
Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115-6017, USA. ahlee@hsph.harvard.edu
Glimcher
Laurie H
LH
D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006505:Hepatitis / Q000503:physiopathology; D006706:Homeostasis; D006801:Humans; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism*; D017510:Protein Folding; D015398:Signal Transduction / Q000502:physiology*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D015003:Yeasts / Q000502:physiology
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D051780:Sterol Regulatory Element Binding Protein 1