• 2018-07
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  • 2021-03
  • Increased circulating and or intracellular FFAs levels are


    Increased circulating and/or intracellular FFAs levels are tightly linked to numerous metabolic disorders including NAFLD. The discovery of ATGL as an essential TAG lipase in many if not all cell types offers a promising pharmacological target to interfere with whole body and organ-specific FA homeostasis. This strategy was followed in a collaboration with the lab of R. Breinbauer at the University of Technology, Graz and our lab, where a small-molecule ATGL inhibitor (designated as “Atglistatin”) was developed and demonstrated to specifically and efficiently inhibit ATGL lipolysis in vitro and in vivo [77]. Intriguingly, dietary administration of Atglistatin protected mice from HFD-induced hepatic steatosis and insulin resistance [78]. Moreover, NAFLD score (number of inflammatory 13(S)-HODE and areas as well as the degree of liver cell ballooning) was strongly reduced in Atglistatin treated mice, which was accompanied by lower plasma alanine-aminotransferase levels and decreased expression of inflammatory and fibrosis marker genes. The administration of Atglistatin resulted in similar distribution of the inhibitor in white adipose and liver tissue. The substantial decline in hepatic TAG levels was unexpected, as liver-specific ATGL ablation provokes massive TAG accumulation. The protection from hepatic TAG accumulation may be the consequence of ATGL inhibition in adipose tissue causing impaired TAG mobilization and reduced FFA flux to the liver. It is also conceivable that inhibition of ATGL activity in 13(S)-HODE the liver can be compensated by the induction of other TAG hydrolyzing enzymes and/or lipophagy, which awaits further clarification. Nevertheless and as aforementioned, decrease hepatic TAG levels, as observed in HFD fed mice specifically lacking ATGL in the adipose tissues [76], strongly indicates that Atglistatin treatment protects from NAFLD via inhibition of adipose lipolysis. Notably, Atglistatin administration does not affect cardiac lipid homeostasis and energy metabolism, which is a hallmark of ATGL-deficient mice, elucidating the administration of Atglistatin as a promising strategy to counteract NAFLD development in humans.
    Targeting ATGL co-regulators
    Targeting HSL and MGL Although HSL catalyzes all three steps of TAG hydrolysis, HSL is essential for the second step of the lipolytic cascade, the hydrolysis of DAG to MAG (Fig. 1) [101]. Mice global lacking HSL are characterized by DAG accumulation in many tissues, but exhibit reduced hepatic TAG levels (and increased insulin sensitivity), indicating that HSL is not essential in liver TAG catabolism [102]. This finding is challenged in humans carrying mutated Hsl alleles, where the lack of HSL protein provokes systemic insulin resistance and hepatic steatosis [103]. This discrepancy was resolved by a very recent study where the impact of adipose- versus liver-specific Hsl deletion on hepatic TAG homeostasis was investigated: Global or adipose-specific deletion of Hsl caused age-dependent hepatic fat accumulation, whereas the lack of HSL specifically in the liver was compatible with normal hepatic TAG homeostasis [104]. Moreover, adipose (or systemic) HSL-deficiency caused progressive lipodystrophy, macrophage infiltration and systemic insulin resistance in aged mice [104]. These phenotypic changes were accompanied by decreased hepatic lipolysis, FAO and VLDL-TG production, which altogether affect hepatic TAG homeostasis. Humans lacking HSL are skinny in appearance and it is conceivable that the metabolic changes presented in HSL-deficient mice play also a role in the development of hepatic steatosis and insulin resistance in humans [103]. Similar to hepatic ATGL ablation, NAFLD caused by the lack of adipose HSL does not trigger hepatic fibrosis and inflammation, which may indicate that reduced ATGL lipolysis may play a role in NAFLD development in HSL mutant mice. Together, these studies implicate that hepatic steatosis in patients carrying mutated Hsl alleles rather originates from lipodystrophy, which then interferes with hepatic lipid and energy metabolism. Besides the hydrolysis of TAG and DAG, HSL also acts as a neutral CE hydrolase. As aforementioned, hepatic HSL-deficiency in mice had no impact on hepatic TAG homeostasis [104]. In contrast, global HSL-deficient mice exhibited CE accumulation on a high cholesterol diet or on the Leptin-deficient background, paralleled by reduced CE hydrolase activities in liver preparations indicative for impaired CE catabolism in the absence of HSL [55]. Moreover, primary hepatocytes from HSL-deficient mice already exhibited increased CE levels and incubation with cholesterol rich low-density lipoprotein further increased CE levels [55] suggesting that HSL participates in hepatic CE catabolism. Another study showed increased CE levels in the liver of HSL-deficient mice even on chow and HFD together with increased expression of the cholesterol transporter ABCA1 in liver tissue, further corroborating a role for HSL in hepatic CE catabolism [105]. The overall increase in plasma cholesterol levels was due to an increase in HDL and VLDL cholesterol levels implicating that global HSL-deficiency interferes with whole body cholesterol homeostasis. The raise in plasma cholesterol of HSL-deficient mice may be an adaption to impaired hepatic CE catabolism and an increase in liver CE content, leading to elevated hepatic ABCA1 expression, which could enhance cholesterol efflux. Whether HSL-deficiency in humans [103] plays a role in hepatic steatosis development and insulin resistance via impaired liver CE catabolism is actually unknown.