• 2019-07
  • 2019-08
  • 2019-09
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  • 2019-11
  • 2020-03
  • 2020-07
  • 2020-08
  • 2021-03
  • br Proteins involved in hepatic neutral lipid mobilization


    Proteins involved in hepatic neutral lipid mobilization
    Targeting ATGL and pharmacological inhibition of ATGL The role of lipolysis in hepatic TAG homeostasis remained enigmatic until the discovery of ATGL as a novel neutral TAG lipase [45]. The generation of ATGL-deficient mice demonstrated ATGL's dominant role in TAG hydrolysis, since these mice exhibited TAG accumulation in cytosolic LDs of many organs and tissues, including the liver [42]. Several follow up studies, where ATGL expression was down regulated or increased in mice via injection of recombinant adenovirus, suggested a role for ATGL in liver TAG catabolism and the supply of FAs as oxidative fuel [68,69]. The critical role of ATGL in hepatic TAG homeostasis was evident from the liver-specific deletion of Atgl, which provoked progressive macrovesicular and microvesicular hepatic steatosis [70], accompanied by massive hepatic TAG accumulation in mice fed either a chow or a high fat diet (HFD). Impaired lipolysis in these mice was linked to decreased FA oxidation, which may further promote hepatic TAG deposition. LDs were also present within cholangiocytes, implicating that ATGL is required for lipolysis in these cells. The observation that TAG accumulation was relatively mild in hepatic tissue of mice globally lacking ATGL [42] as compared to hepatic ATGL-deficiency [70] suggests that impaired adipose tissue FA mobilization and consequently reduced FA flux to the liver prevented severe hepatic TAG accumulation in mice globally lacking ATGL. Particularly interesting, severe hepatic steatosis caused by hepatic ATGL-deficiency was benign and not associated with liver fibrosis and inflammation. Furthermore, impaired hepatic lipolysis did not significantly interfere with VLDL secretion and hepatic insulin sensitivity. These findings suggest that i), lipoprotein TAG incorporation does not depend on the release of FAs from cytosolic LDs and that ii), hepatic TAG accumulation per se is not the main trigger in the development of hepatic insulin resistance, at least in ATGL-mutant mice. Although speculative, impaired TAG catabolism together with reduced FA oxidation (FAO) may lower levels of FFAs in mice with hepatic Atgl-disruption, thereby counteracting the detrimental consequences of increased cellular FFA levels, also referred to as lipotoxicity [71]. In line with such an assumption, the study by Fuchs et al. [72] demonstrated that the global lack of ATGL protected mice from tunicamycin-induced ER stress and hepatic inflammation despite hepatic TAG 9(S)-HODE accumulation. This study also showed that the ratio of palmitic 9(S)-HODE versus oleic acid was lower in the hepatic TAG pool of ATGL-deficient mice. As saturated FAs can trigger ER stress in hepatocyte cell lines [73], the authors hypothesized that the decrease in the relative amount of palmitic acid may counteract the development of ER stress in mice globally lacking ATGL. However, a study by the same laboratory reported that hepatic inflammation increased in ATGL-deficient mice, kept either on a methionine-choline-deficient (MCD) diet to induce NASH or upon injection of lipopolysaccharide to induce acute hepatic inflammation [74]. Interestingly, dietary supplementation with the peroxisome proliferator-activated receptor alpha (PPARα) agonist fenofibrate mitigates hepatic inflammation in both, MCD fed or lipopolysaccharide-injected ATGL-deficient mice. These findings implicate that impaired PPARα signaling, which was shown to exacerbate hepatic inflammation in the MCD mouse model [75], may promote hepatic inflammation in the absence of ATGL. Together these data indicate that hepatic steatosis in ATGL-deficient mice can be a precondition that enhances hepatic inflammation under specific conditions of hepatic stress. Yet, these studies were performed in mice globally lacking ATGL and do not allow to delineate whether the observed changes in hepatic inflammation originate from the lack of ATGL in the liver and/or adipose tissue. In line with this question, we could show that impaired adipose tissue lipolysis due to deletion of ATGL or its co-activator CGI-58 solely in adipose tissue profoundly interferes with hepatic PPARα signaling, encompassing a robust decrease in Fibroblast growth factor 21 (FGF21) expression and reduced ER stress on HFD [76]. Besides its established role as a TAG hydrolase, the study by Taschler et al. [62] demonstrated that REs are also a substrate for ATGL and importantly, inhibition of ATGL enzyme activity increased RE content in HSCs. Moreover, ATGL also efficiently hydrolyzed RE in parallel to TAG, implicating that both TAG and RE can compete for ATGL binding. However, RE levels were unchanged in mice globally lacking ATGL indicating that other enzymes participate in hepatic RE catabolism. Nevertheless, the stimulation of lipolysis in HSCs is linked to the activation and proliferation of HSCs, which is considered to contribute to hepatic fibrosis development [22]. However, feeding mice globally lacking ATGL with a MCD diet led to increased collagen 1 alpha expression, rather indicative for induction of HSC activation than protection of disease progression (from liver steatosis to fibrosis) [74]. Accordingly, it would be interesting to examine whether liver-specific ATGL deletion or overexpression affects hepatic fibrosis progression in mice on MCD diet or upon chemical induction of liver fibrosis likely via changes in HSC metabolism.