Interruption of triacylglycerol synthesis in the endoplasmic reticulum is the initiating event for saturated fatty acid‐induced lipotoxicity in liver cells

Abstract

The aim of the present study was to investigate in detail the molecular mechanisms by which free fatty acids induce liver toxicity in liver cells. HepG2 and Huh7 human liver cell lines were exposed to varying concentrations of stearate (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) stearate, 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 reticulum, apparently because of the formation of a pool of oversaturated intermediates, represents the key initiating event in the mechanism of saturated fatty acid‐induced lipotoxicity.

Zsírsavtúltengés – inzulinrezisztencia és β-sejt-halál

“…Igaz, hogy ennek diglicerid intermediere növelheti a PKC-aktivitást, mégis egyre több adat utal arra, hogy az ectopiás zsírraktározás -a korábban uralkodó nézettel szemben -inkább védő, mintsem kiváltó vagy súlyosbító tényező-je a lipotoxicitásnak [23]. Ha telítetlen zsírsavból lénye-gesen kevesebb áll rendelkezésre, a trigliceridszintézis elakad [24]. Ezen tud segíteni a sejt saját deszaturációs aktivitása.…”

Lipotoxicity in the liver

“…It has been demonstrated in HepG2 and Huh7 human liver cell lines that lipotoxic effect of the saturated stearate is initiated by interruption of triacylglycerol synthesis. Retained capacity to synthesize and accumulate triglycerides in the presence of unsaturated oleate, in fact, turned out to be protective [18] .…”

“…Hindrance of protective fat synthesis favors fatty acid oxidation and leads to excessive ROS generation; The emerging oxidative stress and the increased saturation of membrane lipids trigger the endoplasmic reticulum (ER) stress response, which contributes to insulin resistance and further enhances cell death (dotted lines). The greater hepatotoxicity of saturated vs unsaturated fatty acids has been demonstrated in several studies [18,[22][23][24][25] . Moreover, the unsaturated fatty acids often prove to be protective against SFA-induced toxicity [18,24] .…”

“…The greater hepatotoxicity of saturated vs unsaturated fatty acids has been demonstrated in several studies [18,[22][23][24][25] . Moreover, the unsaturated fatty acids often prove to be protective against SFA-induced toxicity [18,24] . Interruption of triglyceride synthesis, apparently because of the formation of a pool of oversaturated intermediates, seems to be a key event in SFA-induced lipotoxicity.…”

“…Interruption of triglyceride synthesis, apparently because of the formation of a pool of oversaturated intermediates, seems to be a key event in SFA-induced lipotoxicity. Accumulation of stearoyl-CoA and a decreased capacity of triglyceride production have been found in HepG2 and Huh7 human hepatoma cells exposed to stearate [18] . In accordance with its central role in converting SFAs to monounsaturated fatty acids (MUFAs), SCD1 proved to be protective against SFAinduced hepatocyte lipoapoptosis ( Figure 2B).…”