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  • In this report we describe studies of

    2021-01-07

    In this report we describe studies of the effects of peroxisome proliferator-activated receptor γ (PPARγ) and acyl-CoA synthetase (ACSL1) on palmitate-induced ER stress in the human cardiomyocyte-like cell line AC16 [22], which was derived from adult ventricular heart tissue. PPARγ is a nuclear receptor involved in regulation of intracellular lipid storage, and ACSL1 catalyzes esterification of long chain FAs with co-enzyme A — the initial step in fatty LAF-237 metabolism. Although cardiomyocyte specific overexpression of either PPARγ or ACSL1 causes lipid accumulation and cardiac dysfunction, both PPARγ and ASCL1 inhibit inflammation in FA-treated macrophages [23]. Our study shows that PPARγ and ACSL1 can protect cardiomyocytes from ER stress. Moreover we found that oleate (OA), which is usually a non-toxic lipid, induces toxicity if its storage is disrupted by excess intracellular lipolysis.
    Materials and methods
    Results
    Discussion Cardiac lipotoxicity is an important cause of heart failure [3], [15]. One of the mechanisms involved in the pathogenesis of heart failure is ER stress. Here we show that increased ACSL1 and PPARγ expression leads to increased neutral lipid storage in cardiomyocytes and protect against PA-induced ER stress. Increasing NEFA release by overexpression of ATGL increased ER stress. These data further support the hypothesis that neutral lipid storage capacity modulates lipotoxicity. Although accumulation of lipids in non-adipose tissues correlates with markers for impaired cellular function [34], [35], [36], directing FAs to neutral lipid storage in lipid droplets, primarily in the form of TAG, has been shown to protect against lipotoxicity and lipid-induced insulin resistance in various tissues including skeletal muscle, liver and heart [2], [18], [37], [38], [39]. Storage of FAs in TAG limits accumulation of lipid species with greater lipotoxic potential such as DAGs and ceramides (reviewed in [40], [41], [42]). Our findings are similar to those found in vivo; cardiac lipid accumulation does not have lipotoxic consequences when due to exercise training-induced cardiac lipid accumulation [19] and DGAT1 overexpression [19], [43]. These conditions are associated with more TAG formation but less DAG and ceramide. The use of an in vitro system allowed us to study the effects of treatment with PA or OA specifically on cells without the influences of tissue- and organ-interactions. We chose to study the quantitatively most important FAs in plasma [1] and the impact of overexpression of ACSL1 and PPARγ. Our findings are consistent with the observation made in various cell types showing that saturated FAs like PA induce lipotoxic responses, whereas unsaturated FAs like OA do not. OA can even protect against PA-induced toxicity [16], [44], [45], [46], [47]. PA, in contrast to OA, increased the expression of the ER stress markers CHOP and ATF6. OA is a better substrate for DGAT-mediated TAG synthesis [18]. Palmitoyl-CoA may accumulate in mitochondria [44], [48], trigger ROS generation [9], and function as a precursor for ceramide synthesis [13]. ACSL1 and PPARγ overexpression reduced PA-induced ER stress, as demonstrated by the elimination of the PA-induced expression of the ER stress markers CHOP and ATF6. Our findings support those by Miller et al., who showed that inhibition of ACSL1 by triacsin C resulted in a 2-fold increase in PA-mediated apoptosis [49]. Furthermore, Muoio et al., showed that overexpression of ACSL1 in hepatocytes increased incorporation of NEFA into TAGs [50]. Our results are also consistent with animal studies in which cardiac-specific increased expression of ACSL1 [31] or PPARγ [29] increased cardiac TAG levels. Although cardiac PPARγ and ACSL1 overexpression in mice caused toxicity [29], [31], our studies using an in vitro system do not allow us to assess the long-term results of these gene overexpressions. However, our studies do suggest that over the long-term ATGL hydrolysis of neutral stored lipids is likely to promote toxicity. The in vivo studies may also reflect toxic consequences of chronic TAG accumulation that is usually accompanied by accumulation of toxic lipids, such as DAG and ceramide [51].