Abstract
In non-alcoholic fatty liver disease (NAFLD) caused by ectopic lipid accumulation, lipotoxicity is a crucial molecular risk factor. Mechanisms to eliminate lipid overflow can prevent the liver from functional complications. This may involve increased secretion of lipids or metabolic adaptation to ß-oxidation in lipid-degrading organelles such as mitochondria and peroxisomes. In addition to dietary factors, increased plasma fatty acid levels may be due to increased triglyceride synthesis, lipolysis, as well as de novo lipid synthesis (DNL) in the liver. In the present study, we investigated the impact of fatty liver caused by elevated DNL, in a transgenic mouse model with liver-specific overexpression of human sterol regulatory element-binding protein-1c (alb-SREBP-1c), on hepatic gene expression, on plasma lipids and especially on the proteome of peroxisomes by omics analyses, and we interpreted the results with knowledge-based analyses. In summary, the increased hepatic DNL is accompanied by marginal gene expression changes but massive changes in peroxisomal proteome. Furthermore, plasma phosphatidylcholine (PC) as well as lysoPC species were altered. Based on these observations, it can be speculated that the plasticity of organelles and their functionality may be directly affected by lipid overflow.
Highlights
It is well known that mitochondria have a central role in lipid-degrading, but the metabolic function of peroxisomes is becoming more important in order to counteract lipid accumulation in hepatocytes during metabolic stress (Unger et al, 2010; Fransen et al, 2012; Wanders, 2013; Knebel et al, 2015, 2018a; Wanders et al, 2015)
Peroxisomes are specialized organelles involved in Abbreviations: ALT, alanine transaminase; AST, aspartate transaminase; BG, blood glucose; de novo lipid synthesis (DNL), de novo lipogenesis; EFA, essential fatty acids; ER, endoplasmatic reticulum; FFA, free fatty acids; GO, gene ontology; HOMA-%ß, Homeostatic model assessment of ß-cell function (%); HOMA-IR, Homeostatic model assessment of insulin resistance; IR, insulin resistance; LysoPC, Lyso-phosphatidylcholine; MS, mass spectrometry; MUFA, monounsaturated fatty acids; NAFLD, non-alcoholic fatty liver disease; non-essential fatty acids (NEFA), non-saturated fatty acids; PC, phosphatidylcholine; polyunsaturated fatty acids (PUFA), poly unsaturated fatty acids; SCD1, 9 stearoyl-CoA desaturase 1; SFA, saturated fatty acids; SREBP, sterol regulatory element-binding protein; TFA, total fatty acids; TG, triglycerides; UFA, unsaturated fatty acids
The results indicate a differential response pattern depending on the cellular physiology as caused by hepatic lipid accumulation in the models investigated, FIGURE 5 | Hepatic lipid composition of C57Bl6 and alb-SREBP-1c mice at the age of 24 weeks. (A) Fractional composition of liver TFAs and %-change within C57Bl6 and alb-SREBP-1c mice. (B) From the hepatic lipid composition, the sums of non-saturated FA, non-essential FA (C16:0 + cC16:1 + C18:0 + cC18:1), monounsaturated FA, polyunsaturated FA, saturated FA, essential FA [cC18:2 + cC18:3) or elongation index (C18:0/C16:0)], de novo lipogenesis (DNL) index (C16:0/cC18:2), 5 desaturase index, 6 desaturase index, 9 desaturase index, and 9 desaturase index were calculated
Summary
It is well known that mitochondria have a central role in lipid-degrading, but the metabolic function of peroxisomes is becoming more important in order to counteract lipid accumulation in hepatocytes during metabolic stress (Unger et al, 2010; Fransen et al, 2012; Wanders, 2013; Knebel et al, 2015, 2018a; Wanders et al, 2015). The view of peroxisomes has changed from the previously considered role of degradation of branched or very long chain- fatty acids to fatty acids of medium chain length for further metabolic use in mitochondria. It is clear that peroxisomes act in specific anabolic processes, including the synthesis of bile acids for cholesterol clearance and produce ether lipids from lysophosphatidic precursors. The latter precursors were converted to special lipid species, i.e., plasmalogens (Lodhi and Semenkovich, 2014)
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