The impact of genetic stress by ATGL deficiency on the lipidome of lipid droplets from murine hepatocytes

Abstract

In a preceding study, we carried out intervention trials with wild-type (WT) mice fed normal chow, exposed to short-time starvation, or treated with high-fat diet (HFD). The aim was to assess the effect of these forms of nutritional stress on the lipidome of lipid droplets (LDs) isolated from hepatocytes. Lipidomic analysis by LC-MS enabled profi ling of all species from glycerolipid and glycerophospholipid classes and revealed particularly the triacylglycerol (TG) lipidome to be best suited for phenotyping nutritional stresses applied to the animals. In addition, structural analysis by MS/MS at lipid molecular species level provided metabolic relationships characteristic for hepatocyte lipid metabolism ( 1 ). To further probe the phenotypic information potential inherent in the lipidome of hepatocyte LDs, we have now extended the question to genetic stress; we have characterized a mouse model lacking adipocyte triglyceride lipase (ATGL), which shows a marked defect in lipid metabolism in many tissues including the liver . Community's Seventh Framework Programme (FP7/2007 Abbreviations: ATGL, adipocyte triglyceride lipase; CGI-58, comparative gene identifi cation 58; DG, diacylglycerol; FAS, fasted before sacrifi ce; FED, received control chow; HFD, high-fat diet; KO, knockout; LD, lipid droplet; LDA, Lipid Data Analyzer; PC, phosphatidylcholine; PCA, principal component analysis; PC1, principal component 1; PC2, principal component 2; PE, phosphatidylethanolamine; PI, phosphatidylinositol; PS, phosphatidylserine; TG, triacylglycerol; VLC, very long-chain; WT, wild-type; WT-FED, WT-FAS, KO-FED, KO-FAS, hepatocyte LD sample groups from wild-type or knockout mice fed chow or kept in fasted condition, respectively . The research leading to these results received funding from the European

Nonalcoholic fatty liver disease is associated with an almost twofold increased risk of incident type 2 diabetes and metabolic syndrome. Evidence from a systematic review and meta‐analysis

“…It has been demonstrated that visceral obesity without a concomitant increase in hepatic fat content does not cause metabolic complications, such as systemic and hepatic IR and atherogenic dyslipidemia . As regards to this, recent experimental evidence supports a key role for hepatic diacylglycerol activation of protein kinase C epsilon in triggering hepatic IR . Dysregulation of intra‐hepatic lipid droplet metabolism may influence the intracellular compartmentation of diacylglycerol, which dictates whether or not protein kinase C epsilon will translocate to the plasma membrane, so promoting lipotoxicity and hepatic IR.…”

Lipid droplet functions beyond energy storage

“…In murine hepatocytes, the FA composition and degree of saturation in the triglyceride fraction of purified LDs are both very sensitive to nutritional and genetic perturbations [24, 87, 88]. A common denominator associated with LD induction in non-adipose tissues is cell stress, which can be triggered by excess free FAs, nutrient deprivation and/or redox imbalances.…”

Proteomic and genomic studies of non-alcoholic fatty liver disease - clues in the pathogenesis

“…Further evaluation suggested that an enrichment of oleic acid in the TG pool plays the main role for ATGL in protection from potentially harmful consequences of ER stress [103] . Furthermore, ATGL-KO animal model demonstrated a high insulin sensitivity despite liver TG storage [102] . Therefore, the progressions of NAFLD in obese and diabetes patients have a distinguishable phenotypic imprint on the hepatocyte lipidome.…”

“…Adipose tissue triglyceride lipase (ATGL) has been found to be a ratelimiting enzyme for degradation of TG and has been implicated in the pathogenesis and progression of NAFLD. A deficiency of ATGL was proposed to lead to TG accumulation in many organs, including the liver [102,103] . In murine model, ATGL knock out (ATGL-KO) mice demonstrated increased hepatic lipids accumulation during induced-ER stress but suppressed gene expression of inflammatory markers.…”

“…Identified the patients group who is more susceptible to aggressive diseases Dubuquoy et al [95] 2013 PNPLA3 polymorphism is more likely to influence lipid content and liver disease severity but not insulin resistance A less clear association of insulin resistance with PNPLA3 polymorphism ATGL Chitraju et al [102] 2013 Demonstrated that ATGL-KO animal models have high insulin sensitivity An accumulation of TG could be a protective mechanism in NAFLD ApoC3…”