ABSTRACT
BACKGROUND: Inhibition of proprotein convertase subtilisin/kexin type 9 with alirocumab decreases plasma lipoprotein(a) [Lp(a)] levels. The kinetic mechanism for lowering Lp(a) by alirocumab may differ according to pre-treatment apolipoprotein(a) [apo(a)] levels. METHODS: The effect of 12-week alirocumab (150 mg subcutaneously fortnightly) on the kinetics of apo(a) was compared in statin-treated patients with high (n = 10) and very high Lp(a) concentrations (n = 11). RESULTS: In patients with high apo(a) concentrations, alirocumab lowered plasma apo(a) pool size (-17%, p < 0.01) chiefly by increasing the fractional catabolic rate (FCR) of apo(a) (+27%, p < 0.001). By contrast in patients with very high apo(a) concentrations, alirocumab significantly lowered plasma apo(a) pool size (-32%, p < 0.001) by both increasing apo(a) FCR (+30%, p < 0.001) and lowering production rate (-11%, p < 0.05). CONCLUSIONS: In statin-treated patients with very high apo(a) concentrations, alirocumab lowers plasma Lp(a) concentration by a dual mode of action that increases the clearance and decreases the production of Lp(a) particles.
Subject(s)
Hydroxymethylglutaryl-CoA Reductase Inhibitors , Lipoprotein(a) , Antibodies, Monoclonal, Humanized , Apoprotein(a)/metabolism , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Proprotein Convertase 9ABSTRACT
To elucidate the molecular mechanisms underlying non-alcoholic fatty liver disease (NAFLD), we recruited 86 subjects with varying degrees of hepatic steatosis (HS). We obtained experimental data on lipoprotein fluxes and used these individual measurements as personalized constraints of a hepatocyte genome-scale metabolic model to investigate metabolic differences in liver, taking into account its interactions with other tissues. Our systems level analysis predicted an altered demand for NAD+ and glutathione (GSH) in subjects with high HS Our analysis and metabolomic measurements showed that plasma levels of glycine, serine, and associated metabolites are negatively correlated with HS, suggesting that these GSH metabolism precursors might be limiting. Quantification of the hepatic expression levels of the associated enzymes further pointed to altered de novo GSH synthesis. To assess the effect of GSH and NAD+ repletion on the development of NAFLD, we added precursors for GSH and NAD+ biosynthesis to the Western diet and demonstrated that supplementation prevents HS in mice. In a proof-of-concept human study, we found improved liver function and decreased HS after supplementation with serine (a precursor to glycine) and hereby propose a strategy for NAFLD treatment.
Subject(s)
Glutathione/metabolism , Lipoproteins/metabolism , Metabolomics/methods , NAD/metabolism , Non-alcoholic Fatty Liver Disease/genetics , Serine/administration & dosage , Animals , Disease Models, Animal , Female , Gene Expression Regulation, Enzymologic , Genome , Glycine/blood , Humans , Liver/enzymology , Liver/metabolism , Male , Mice , Middle Aged , Non-alcoholic Fatty Liver Disease/diet therapy , Non-alcoholic Fatty Liver Disease/metabolism , Patient-Specific Modeling , Serine/blood , Serine/therapeutic useABSTRACT
We study the associations between apoA-II fractional catabolic rate (FCR) and the kinetics of VLDL subspecies and apoA-I and show that, in abdominally obese individuals, apoA-II FCR is positively and independently associated with both apoA-I FCR and VLDL1-TG indirect FCR.
Subject(s)
Apolipoprotein A-II/metabolism , Lipoproteins, HDL/metabolism , Lipoproteins, VLDL/metabolism , Metabolic Syndrome/etiology , Metabolic Syndrome/metabolism , Obesity, Abdominal/complications , Adult , Aged , Female , Humans , Insulin Resistance , Kinetics , Male , Metabolic Syndrome/pathology , Middle AgedABSTRACT
CONTEXT: Low plasma high-density lipoprotein (HDL) cholesterol is a major abnormality in abdominal obesity. This relates due to accelerated HDL catabolism, but the underlying mechanism requires further elucidation. The relationships between HDL catabolism and other variables that may be modified in abdominal obesity, such as very low-density lipoprotein (VLDL) subspecies (VLDL1, VLDL2) kinetics, liver fat, or visceral adiposity, remain to be investigated. OBJECTIVES: Our aim was to study the associations between HDL apolipoprotein (apo)-A-I fractional catabolic rate (FCR) and the kinetics of VLDL subspecies and estimates of liver and visceral and sc fat. DESIGN: We carried out a multicenter in vivo kinetic study using stable isotopes (deuterated leucine and glycerol) in 62 individuals with abdominal obesity. RESULTS: In a multivariate analysis, among the morphological and biological parameters that may predict apoA-I FCR, liver fat (ß = .400, P = .003), and VLDL1-apoB (ß = .307, P = .020) were independently associated with apoA-I FCR. In a multivariate analysis, among the kinetic parameters, VLDL1-triglycerides (TGs) indirect FCR (ß = -.357, P = .001), VLDL1-TG production rate (ß = 0.213, P = .048), and apoA-II FCR (ß = .667, P < .0001) were independently associated with apoA-I FCR. After adjustment for VLDL1-TG production rate, liver fat was no more correlated with apoA-I FCR. No association between apoA-I FCR and visceral fat was observed. CONCLUSIONS: We show that VLDL1 is an important independent determinant of apoA-I FCR and more precisely that apoA-I FCR is independently associated with both catabolism and the production of VLDL1-TG. In addition, we show an association between liver fat and apoA-I FCR that is mostly mediated by VLDL1-TG production. These data indicate that, in abdominal obesity, dysfunctional VLDL1 metabolism is an important modulator of HDL apoA-I catabolism.
