Different fatty acids inhibit apoB100 secretion by different pathways: unique roles for ER stress, ceramide, and autophagy

Jorge Matias Caviglia,Constance Gayet,Tsuguhito Ota,Antonio Hernandez-Ono,Donna M Conlon,Hongfeng Jiang,Edward A Fisher,Henry N Ginsberg

doi:10.1194/jlr.m016931

Jorge Matias Caviglia, Constance Gayet + Show 6 more

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https://doi.org/10.1194/jlr.m016931

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Although short-term incubation of hepatocytes with oleic acid (OA) stimulates secretion of apolipoprotein B100 (apoB100), exposure to higher doses of OA for longer periods inhibits secretion in association with induction of endoplasmic reticulum (ER) stress. Palmitic acid (PA) induces ER stress, but its effects on apoB100 secretion are unclear. Docosahexaenoic acid (DHA) inhibits apoB100 secretion, but its effects on ER stress have not been studied. We compared the effects of each of these fatty acids on ER stress and apoB100 secretion in McArdle RH7777 (McA) cells: OA and PA induced ER stress and inhibited apoB100 secretion at higher doses; PA was more potent because it also increased the synthesis of ceramide. DHA did not induce ER stress but was the most potent inhibitor of apoB100 secretion, acting via stimulation of autophagy. These unique effects of each fatty acid were confirmed when they were infused into C57BL6J mice. Our results suggest that when both increased hepatic secretion of VLDL apoB100 and hepatic steatosis coexist, reducing ER stress might alleviate hepatic steatosis but at the expense of increased VLDL secretion. In contrast, increasing autophagy might reduce VLDL secretion without causing steatosis.

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Short-term incubation of hepatocytes with oleic acid (OA) stimulates secretion of apolipoprotein B100, exposure to higher doses of OA for longer periods inhibits secretion in association with induction of endoplasmic reticulum (ER) stress
OA and Palmitic acid (PA), but not Docosahexaenoic acid (DHA), induce ER stress in McArdle RH7777 (McA) cells We demonstrated previously that hepatic ER stress was induced by loading McA cells with OA at high physiologic concentrations for more than 6 h [6]
Greater ER stress in McA cells transfected with stearoyl-CoA desaturase 1 (SCD1) small interfering RNAs (siRNA) was associated with greater inhibition of apolipoprotein B100 (apoB100) secretion when incubated with PA (Fig. 5D, right); the level of SCD1 mRNA had no effect on OA-induced inhibition of apoB100 secretion (Fig. 5D, left)

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Introduction

Short-term incubation of hepatocytes with oleic acid (OA) stimulates secretion of apolipoprotein B100 (apoB100), exposure to higher doses of OA for longer periods inhibits secretion in association with induction of endoplasmic reticulum (ER) stress. To compare the effects of different fatty acids on apoB100 secretion and examine the mechanisms for those effects, we incubated McA cells for 16 h with OA, PA, or DHA at concentrations ranging from 0.2 to 1.2 mM.

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