Loss-of-function (LOF) mutations in ANGPTL3, an inhibitor of
lipoprotein lipase (LPL), cause a drastic reduction of serum
lipoproteins and protect against the development of atherosclerotic
cardiovascular disease. Therefore, ANGPTL3 is a promising
therapy target. We characterized the impacts of ANGPTL3 depletion on the immortalized human hepatocyte (IHH) transcriptome, lipidome and human plasma
lipoprotein lipidome. The transcriptome of ANGPTL3 knock-down (KD) cells showed altered expression of several pathways related to lipid metabolism. Accordingly, ANGPTL3 depleted IHH displayed changes in cellular overall
fatty acid (FA) composition and in the
lipid species composition of several
lipid classes, characterized by abundant n-6 and n-3 polyunsaturated FAs (PUFAs). This PUFA increase coincided with an elevation of
lipid mediators, among which there were species relevant for resolution of
inflammation, protection from lipotoxic and
hypoxia-induced ER stress, hepatic steatosis and
insulin resistance or for the recovery from cardiovascular events.
Cholesterol esters were markedly reduced in ANGPTL3 KD IHH, coinciding with suppression of the SOAT1
mRNA and
protein. ANGPTL3 LOF caused alterations in plasma
lipoprotein FA and
lipid species composition. All
lipoprotein fractions of the ANGPTL3 LOF subjects displayed a marked drop of 18:2n-6, while several highly unsaturated
triacylglycerol (TAG) species were enriched. The present work reveals distinct impacts of ANGPTL3 depletion on the hepatocellular lipidome, transcriptome and
lipid mediators, as well as on the lipidome of
lipoproteins isolated from plasma of ANGPTL3-deficient human subjects. It is important to consider these lipidomics and transcriptomics findings when targeting ANGPTL3 for
therapy and translating it to the human context.