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How does protein misfolding in the endoplasmic reticulum affect lipid metabolism in the liver?

Wang, Shiyu; Kaufman, Randal J.

Current Opinion in Lipidology: April 2014 - Volume 25 - Issue 2 - p 125–132
doi: 10.1097/MOL.0000000000000056
GENETICS AND MOLECULAR BIOLOGY: Edited by Robert A. Hegele

Purpose of review: The endoplasmic reticulum (ER) maintains cellular metabolic homeostasis by coordinating protein synthesis, secretion activities, lipid biosynthesis and calcium (Ca2+) storage. In this review, we will discuss how altered ER homeostasis contributes to dysregulation of hepatic lipid metabolism and contributes to liver-associated metabolic diseases.

Recent findings: Perturbed ER functions or accumulation of unfolded protein in the ER leads to the activation of the unfolded protein response (UPR) to protect the cell from ER stress. Recent findings pinpoint the key regulatory role of the UPR in hepatic lipid metabolism and demonstrate the potential causal mechanism of ER stress in metabolic dysregulation including diabetes and obesity.

Summary: A wide range of factors can alter the protein-folding environment in the ER of hepatocytes and contribute to dysregulation of hepatic lipid metabolism and liver disease. The UPR constitutes a series of adaptive programs that preserve ER protein-folding environment and maintain hepatic lipid homeostasis. Signaling components of the UPR are emerging as potential targets for intervention and treatment of human liver-associated metabolic diseases.

Degenerative Disease Research, Center for Neuroscience, Aging, and Stem Cell Research, Sanford-Burnham Medical Research Institute, La Jolla, California, USA

Correspondence to Randal J. Kaufman, 92037 La Jolla, USA. Tel: +1 858 795 5149; fax: +1 858 795 5273; e-mail: rkaufman@sanfordburnham.org

© 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins