Tài liệu Báo cáo khoa học: SREBPs: physiology and pathophysiology of the SREBP family ppt

MINIREVIEW

SREBPs: physiology and pathophysiology of the

SREBP family

Hitoshi Shimano

Department of Internal Medicine (Endocrinoglogy and Metabolism), Graduate School of Comprehensive Human Sciences, University of

Tsukuba, Japan

SREBP-2 and sterol regulation

The sterol regulatory element-binding protein (SREBP)

family, originally identified as basic helix–loop–helix

(bHLH) leucine zipper transcription factors by Gold￾stein and Brown, is involved in the regulation of genes

participating in cholesterol biosynthesis and low-density

lipoprotein receptor synthesis [1,2]. They are now estab￾lished as global regulators of lipid synthesis. What

makes this bHLH family unique is that SREBPs are syn￾thesized and located on the endoplasmic reticulum (ER)

membrane in their precursor form. To exert transcrip￾tional activities, the active N-terminal region of the

bHLH needs to undergo proteolytic cleavage for nuclear

translocation. Sterol regulation is mainly attributed to

this cleavage activity, depending on cellular cholesterol

levels. The SREBP cleavage-activating protein (SCAP)

functions as a cholesterol sensor. When the cellular cho￾lesterol levels are depleted, SCAP binds to and escorts

SREBP in COPII vesicles to the Golgi apparatus, where

the site 1 and site 2 proteases cleave the SREBPs [3,4].

Upon restoration of cellular cholesterol, Insig, another

key regulator of ER membrane proteins, traps and

retains the SREBP–SCAP complex at the ER to inhibit

SREBP cleavage in the Golgi, thus downregulating

sterol and low-density lipoprotein receptor biosynthesis.

Keywords

cholesterol; diabetes; dyslipidemia; fatty

acids; fatty liver; insulin resistance;

lipotoxicity; metabolic syndrome; SREBP;

trigylcerides

Correspondence

H. Shimano, Department of Internal

Medicine (Endocrinoglogy and Metabolism),

Graduate School of Comprehensive Human

Sciences, University of Tsukuba,

1-1-1 Tennodai, Tsukuba, 305-8575, Japan

Fax: +81 29 853 3174

Tel: +81 29 853 3053

E-mail: [email protected],

[email protected]

(Received 2 August 2008, revised 11

November 2008, accepted 18 November

2008)

doi:10.1111/j.1742-4658.2008.06806.x

Sterol regulatory element-binding proteins (SREBPs) have been established

as physiological regulators of lipid synthesis. The molecular mechanisms by

which cellular sterol balance and nutritional states regulate SREBP acti￾vities are the current research focus of this field. Meanwhile, it has been

shown that overnutrition or disturbed energy balance causes accumulation

of tissue lipids, leading to metabolic disorders, often referred to as ‘lipotox￾icity’. In this overview, I discuss the pathological aspects of SREBPs, which

contribute to lipotoxicity in a wide variety of organs, including hepatic

insulin resistance in hepatosteatosis, impaired insulin secretion in pancreatic

b-cells, diabetic nephropathy, cardiac arrythmiasis, and obesity.

Abbreviations

bHLH, basic helix–loop–helix; ER, endoplasmic reticulum; IRS-2, insulin receptor substrate-2; PUFA, polyunsaturated fatty acid; SCAP, sterol

regulatory element-binding protein cleavage-activating protein; SREBP, sterol regulatory element-binding protein.

616 FEBS Journal 276 (2009) 616–621 ª 2008 The Author Journal compilation ª 2008 FEBS