Cover Story Current Issue
Altered amino acid metabolism is increasingly appreciated as a key driver in the pathology of multiple diseases, including metabolic syndrome, cancer, and neurological disease. Sphingolipids (SLs) are synthesized from serine and fatty acyl-CoAs by serine palmitoyltransferase (SPT) and are critical signaling molecules and membrane components that are enriched in the nervous system and retina. When serine levels are low, alanine (or glycine) is used as a substrate by SPT to yield non-canonical 1-deoxysphingolipids (doxSLs) that drive neuropathy and cellular dysfunction through diverse mechanisms. This highlights a potential mechanism for crosstalk between amino acid metabolism and SL biosynthesis in the context of neurological dysfunction. Numerous heritable neurological and retinal disorders are causative or linked to mutations in genes encoding SL-metabolizing enzymes, including amyotrophic lateral sclerosis (ALS), Tay-Sachs, Niemann-Pick disease, Gaucher disease, Macular telangiectasia type II (MacTel), and hereditary sensory and autonomic neuropathy type 1 (HSAN1).
Courtney R. Green, Roberto Bonelli, Brendan R.E. Ansell, Simone Tzaridis, ... Marin L. Gantner
Current Issue
Angiopoietin-like 4 governs diurnal lipoprotein lipase activity in brown adipose tissue
Objective
Brown adipose tissue (BAT) burns fatty acids (FAs) to produce heat, and shows diurnal oscillation in glucose and triglyceride (TG)-derived FA-uptake, peaking around wakening. Here we aimed to gain insight in the diurnal regulation of metabolic BAT activity.
Methods
RNA-sequencing, chromatin immunoprecipitation (ChIP)-sequencing, and lipidomics analyses were performed on BAT samples of wild type C57BL/6J mice collected at 3-hour intervals throughout the day. Knockout and overexpression models were used to study causal relationships in diurnal lipid handling by BAT.
Results
We identified pronounced enrichment of oscillating genes involved in extracellular lipolysis in BAT, accompanied by oscillations of FA and monoacylglycerol content. This coincided with peak lipoprotein lipase (Lpl) expression, and was predicted to be driven by peroxisome proliferator-activated receptor gamma (PPARγ) activity. ChIP-sequencing for PPARγ confirmed oscillation in binding of PPARγ to Lpl. Of the known LPL-modulators, angiopoietin-like 4 (Angptl4) showed the largest diurnal amplitude opposite to Lpl, and both Angptl4 knockout and overexpression attenuated oscillations of LPL activity and TG-derived FA-uptake by BAT.
Conclusions
Our findings highlight involvement of PPARγ and a crucial role of ANGPTL4 in mediating the diurnal oscillation of TG-derived FA-uptake by BAT, and imply that time of day is essential when targeting LPL activity in BAT to improve metabolic health.
Angiopoietin-like 4 governs diurnal lipoprotein lipase activity in brown adipose tissue
Objective
Brown adipose tissue (BAT) burns fatty acids (FAs) to produce heat, and shows diurnal oscillation in glucose and triglyceride (TG)-derived FA-uptake, peaking around wakening. Here we aimed to gain insight in the diurnal regulation of metabolic BAT activity.
Methods
RNA-sequencing, chromatin immunoprecipitation (ChIP)-sequencing, and lipidomics analyses were performed on BAT samples of wild type C57BL/6J mice collected at 3-hour intervals throughout the day. Knockout and overexpression models were used to study causal relationships in diurnal lipid handling by BAT.
Results
We identified pronounced enrichment of oscillating genes involved in extracellular lipolysis in BAT, accompanied by oscillations of FA and monoacylglycerol content. This coincided with peak lipoprotein lipase (Lpl) expression, and was predicted to be driven by peroxisome proliferator-activated receptor gamma (PPARγ) activity. ChIP-sequencing for PPARγ confirmed oscillation in binding of PPARγ to Lpl. Of the known LPL-modulators, angiopoietin-like 4 (Angptl4) showed the largest diurnal amplitude opposite to Lpl, and both Angptl4 knockout and overexpression attenuated oscillations of LPL activity and TG-derived FA-uptake by BAT.
Conclusions
Our findings highlight involvement of PPARγ and a crucial role of ANGPTL4 in mediating the diurnal oscillation of TG-derived FA-uptake by BAT, and imply that time of day is essential when targeting LPL activity in BAT to improve metabolic health.
2021 impact factor: 8.568
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