The Emerging Role of Fat-inducing Transcript 2 in Endoplasmic Reticulum Proteostasis and Lipoprotein Biogenesis

Overview

Journal Curr Opin Lipidol

Specialty Biochemistry

Date 2024 Aug 22

PMID 39172716

Authors

Jeffrey L Brodsky

Anuradha Iyer

Konstantinos I Fortounas

Edward A Fisher

Affiliations

Soon will be listed here.

Abstract

Purpose Of Review: This review examines the evolving role of the fat-inducing transcript 2 (FIT2) protein in lipid droplet (LD) biology and its broader implications in cellular physiology and disease. With recent advancements in understanding FIT2 function across various model systems, this review provides a timely synthesis of its mechanisms and physiological significance.

Recent Findings: FIT2, an endoplasmic reticulum (ER)-resident protein, has been established as a critical regulator of LD formation in diverse organisms, from yeast to mammals. It facilitates LD biogenesis by sequestering diacylglycerol (DAG) and potentially influencing ER membrane dynamics. Beyond its role in lipid metabolism, FIT2 intersects with the ER-associated degradation (ERAD), is critical for protein homeostasis, and is linked to the unfolded protein response (UPR). Dysregulation of FIT2 has also been linked to metabolic disorders such as insulin resistance and lipodystrophy, highlighting its clinical relevance.

Summary: Insights into FIT2 function underscore its pivotal role in LD formation and lipid homeostasis. Understanding its involvement in ER proteostasis and very low density lipoprotein biogenesis has broad implications for metabolic diseases and cancer. Therapeutic strategies targeting FIT2 may offer novel approaches to modulate lipid metabolism and mitigate associated pathologies. Further research is needed to elucidate the full spectrum of FIT2's interactions within cellular lipid and protein networks, potentially uncovering new therapeutic avenues for metabolic and ER stress-related disorders.

References

Zheng X, Ho Q, Chua M, Stelmashenko O, Yeo X, Muralidharan S . Destabilization of β Cell FIT2 by saturated fatty acids alter lipid droplet numbers and contribute to ER stress and diabetes. Proc Natl Acad Sci U S A. 2022; 119(11):e2113074119. PMC: 8931238. DOI: 10.1073/pnas.2113074119. View

Choudhary V, Golani G, Joshi A, Cottier S, Schneiter R, Prinz W . Architecture of Lipid Droplets in Endoplasmic Reticulum Is Determined by Phospholipid Intrinsic Curvature. Curr Biol. 2018; 28(6):915-926.e9. PMC: 5889118. DOI: 10.1016/j.cub.2018.02.020. View

Chen Y, Ji L, Wang Y, Guo X . High FITM2 expression promotes cell migration ability of hepatocellular carcinoma by regulating the formation of caveolae and indicates poor patient survival. Histol Histopathol. 2021; 36(10):1085-1092. DOI: 10.14670/HH-18-382. View

van Zwol W, van de Sluis B, Ginsberg H, Kuivenhoven J . VLDL Biogenesis and Secretion: It Takes a Village. Circ Res. 2024; 134(2):226-244. PMC: 11284300. DOI: 10.1161/CIRCRESAHA.123.323284. View

Lawson K, Sousa C, Zhang X, Kim E, Akthar R, Caumanns J . Functional genomic landscape of cancer-intrinsic evasion of killing by T cells. Nature. 2020; 586(7827):120-126. PMC: 9014559. DOI: 10.1038/s41586-020-2746-2. View

Goh V, Tan J, Tan B, Seow C, Ong W, Lim Y . Postnatal Deletion of Fat Storage-inducing Transmembrane Protein 2 (FIT2/FITM2) Causes Lethal Enteropathy. J Biol Chem. 2015; 290(42):25686-99. PMC: 4646211. DOI: 10.1074/jbc.M115.676700. View

Christianson J, Olzmann J, Shaler T, Sowa M, Bennett E, Richter C . Defining human ERAD networks through an integrative mapping strategy. Nat Cell Biol. 2011; 14(1):93-105. PMC: 3250479. DOI: 10.1038/ncb2383. View

Wetterau J, ZILVERSMIT D . A triglyceride and cholesteryl ester transfer protein associated with liver microsomes. J Biol Chem. 1984; 259(17):10863-6. View

Fun X, Thibault G . Lipid bilayer stress and proteotoxic stress-induced unfolded protein response deploy divergent transcriptional and non-transcriptional programmes. Biochim Biophys Acta Mol Cell Biol Lipids. 2019; 1865(1):158449. DOI: 10.1016/j.bbalip.2019.04.009. View

10.

Nejatfard A, Wauer N, Bhaduri S, Conn A, Gourkanti S, Singh N . Derlin rhomboid pseudoproteases employ substrate engagement and lipid distortion to enable the retrotranslocation of ERAD membrane substrates. Cell Rep. 2021; 37(3):109840. PMC: 8641752. DOI: 10.1016/j.celrep.2021.109840. View

11.

Olofsson S, Stillemark-Billton P, Asp L . Intracellular assembly of VLDL: two major steps in separate cell compartments. Trends Cardiovasc Med. 2001; 10(8):338-45. DOI: 10.1016/s1050-1738(01)00071-8. View

12.

Dashti Z, Yousefi Z, Kiani P, Taghizadeh M, Maleki M, Borji M . Autophagy and the unfolded protein response shape the non-alcoholic fatty liver landscape: decoding the labyrinth. Metabolism. 2024; 154:155811. DOI: 10.1016/j.metabol.2024.155811. View

13.

Agrawal M, Yeo C, Shabbir A, Chhay V, Silver D, Magkos F . Fat storage-inducing transmembrane protein 2 (FIT2) is less abundant in type 2 diabetes, and regulates triglyceride accumulation and insulin sensitivity in adipocytes. FASEB J. 2018; 33(1):430-440. DOI: 10.1096/fj.201701321RR. View

14.

Feng B, Yao P, Li Y, Devlin C, Zhang D, Harding H . The endoplasmic reticulum is the site of cholesterol-induced cytotoxicity in macrophages. Nat Cell Biol. 2003; 5(9):781-92. DOI: 10.1038/ncb1035. View

15.

Olofsson S, Asp L, Boren J . The assembly and secretion of apolipoprotein B-containing lipoproteins. Curr Opin Lipidol. 1999; 10(4):341-6. DOI: 10.1097/00041433-199908000-00008. View

16.

Moir R, Gross D, Silver D, Willis I . SCS3 and YFT2 link transcription of phospholipid biosynthetic genes to ER stress and the UPR. PLoS Genet. 2012; 8(8):e1002890. PMC: 3426550. DOI: 10.1371/journal.pgen.1002890. View

17.

Yap W, Shyu Jr P, Gaspar M, Jesch S, Marvalim C, Prinz W . The yeast homologs are necessary to maintain cellular proteostasis and membrane lipid homeostasis. J Cell Sci. 2020; 133(21). PMC: 7657468. DOI: 10.1242/jcs.248526. View

18.

Gusarova V, Brodsky J, Fisher E . Apolipoprotein B100 exit from the endoplasmic reticulum (ER) is COPII-dependent, and its lipidation to very low density lipoprotein occurs post-ER. J Biol Chem. 2003; 278(48):48051-8. DOI: 10.1074/jbc.M306898200. View

19.

Houten S, Wanders R . A general introduction to the biochemistry of mitochondrial fatty acid β-oxidation. J Inherit Metab Dis. 2010; 33(5):469-77. PMC: 2950079. DOI: 10.1007/s10545-010-9061-2. View

20.

Kadereit B, Kumar P, Wang W, Miranda D, Snapp E, Severina N . Evolutionarily conserved gene family important for fat storage. Proc Natl Acad Sci U S A. 2007; 105(1):94-9. PMC: 2224239. DOI: 10.1073/pnas.0708579105. View