Tài liệu Báo cáo khoa học: Interruption of triacylglycerol synthesis in the endoplasmic reticulum is

Interruption of triacylglycerol synthesis in the

endoplasmic reticulum is the initiating event for saturated

fatty acid-induced lipotoxicity in liver cells

Michalis D. Mantzaris1

, Epameinondas V. Tsianos2 and Dimitrios Galaris1

1 Laboratory of Biological Chemistry, University of Ioannina Medical School, Greece

2 First Division of Internal Medicine and Hepato-gastroenterology Unit, University of Ioannina Medical School, Greece

Introduction

Dietary habits in the Western world have changed dras￾tically during the last few decades, and this change cor￾relates with increasing levels of obesity, implying that

diet may be associated with the development of insulin

resistance, type 2 diabetes, cardiovascular disease and

other pathologies in the general population [1]. Con￾sumption of food rich in fat causes qualitative and

quantitative changes in serum free fatty acid (FFA) lev￾els, and increases the rate of uptake and accumulation

of lipids in nonadipose tissues such as the liver, which

is the main lipid-metabolizing organ. Inappropriate

accumulation of excess lipids in liver cells in the form

of lipid droplets has been proposed to lead to dysfunc￾tion of hepatocytes and, consequently, to serious path￾ological complications [2,3]. Nonalcoholic fatty liver

disease (NAFLD) is a term used to characterize a spec￾trum of pathological changes ranging from simple fatty

infiltration (steatosis) to hepatic steatosis accompanied

Keywords

endoplasmic reticulum stress; lipoapoptosis;

nonalcoholic fatty liver disease (NAFLD);

oleate; stearate

Correspondence

D. Galaris, Laboratory of Biological

Chemistry, University of Ioannina Medical

School, 451 10 Ioannina, Greece

Fax: +30 26510 07868

Tel: +30 26510 07562

E-mail: [email protected]

(Received 14 October 2010, revised 16

November 2010, accepted 24 November

2010)

doi:10.1111/j.1742-4658.2010.07972.x

The aim of the present study was to investigate in detail the molecular mecha￾nisms by which free fatty acids induce liver toxicity in liver cells. HepG2 and

Huh7 human liver cell lines were exposed to varying concentrations of stea￾rate (18:0), oleate (18:1), or mixtures of the two fatty acids, and the effects on

cell proliferation, lipid droplet accumulation and induction of endoplasmic

reticulum stress and apoptosis were evaluated. It was observed that: (a) stea￾rate, but not oleate, inhibited cell proliferation and induced cell death; (b)

stearate-induced cell death had the characteristics of endoplasmic reticulum

stress-mediated and mitochondrial-mediated apoptosis; (c) the activation of

stearate in the form of stearoyl-CoA was a necessary step for the lipotoxic

effect; (d) the capacity of cells to produce and accumulate triacylglycerols in

the form of lipid droplets was interrupted following exposure to stearate,

whereas it proceeded normally in oleate-treated cells; and (e) the presence of

relatively low amounts of oleate protected cells from stearate-induced toxicity

and restored the ability of the cells to accumulate triacylglycerols. Our data

suggest that interruption of triacylglycerol synthesis in the endoplasmic retic￾ulum, apparently because of the formation of a pool of oversaturated inter￾mediates, represents the key initiating event in the mechanism of saturated

fatty acid-induced lipotoxicity.

Abbreviations

ACS, long-chain acyl-CoA synthetase; ATF4, activating transcription factor 4; BrdU, bromodeoxyuridine; CHOP, CCAAT ⁄ enhancer-binding

protein homologous protein; DAG, diacylglycerol; ER, endoplasmic reticulum; eIF2a, eukaryotic translation initiation factor 2a;

FITC, fluorescein isothiocyanate; FFA, free fatty acid; JNK, c-Jun N-terminal kinase; NAFLD, nonalcoholic fatty liver disease; PERK,

RNA-dependent protein kinase-like endoplasmic reticulum eukaryotic initiation factor-2a kinase; PI, propidium iodide; SD, standard deviation;

SFA, saturated fatty acid; TAG, triacylglycerol; TrC, triacsin C; UFA, unsaturated fatty acid.

FEBS Journal 278 (2011) 519–530 ª 2010 The Authors Journal compilation ª 2010 FEBS 519