Low apolipoprotein A-I levels in Friedreich’s ataxia and in frataxin-deficient cells: Implications for therapy

Abstract

Friedreich’s ataxia (FA) is an autosomal recessive neurodegenerative disorder, which results primarily from reduced expression of the mitochondrial protein frataxin. FA has an estimated prevalence of one in 50,000 in the population, making it the most common hereditary ataxia. Paradoxically, mortality arises most frequently from cardiomyopathy and cardiac failure rather than from neurological effects. Decreased high-density lipoprotein (HDL) and apolipoprotein A-I (ApoA-l) levels in the general population are associated with an increased risk of mortality from cardiomyopathy and heart failure. However, the pathophysiology of heart disease in FA is non-vascular and there are conflicting data on HDL-cholesterol in FA. Two studies have shown a decrease in HDL-cholesterol compared with controls and two have shown there was no difference between FA and controls. One also showed that there was no difference in serum Apo-A-I levels in FA when compared with controls. Using a highly specific stable isotope dilution mass spectrometry-based assay, we demonstrated a 21.6% decrease in serum ApoA-I in FA patients (134.8 mg/dL, n = 95) compared with non-affected controls (172.1 mg/dL, n = 95). This is similar to the difference in serum ApoA-I levels between non-smokers and tobacco smokers. Knockdown of frataxin by > 70% in human hepatoma HepG2 cells caused a 20% reduction in secreted ApoA-I. Simvastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor caused a 200% increase in HMG-CoA in the control HepG2 cells with a similar increase in the frataxin knockdown HepG2 cells, back to levels found in the control cells. There was a concomitant 20% increase in secreted ApoA-I to levels found in the control cells that were treated with simvastatin. This study provides compelling evidence that ApoA-I levels are reduced in FA patients compared with controls and suggest that statin treatment would normalize the ApoA-I levels.

Safety and Efficacy of Omaveloxolone in Friedreich Ataxia (MOXIe Study)

“…Although the liver is normal for clinical care in FA, liver frataxin levels are among the highest in the body and are decreased in animal models of FA 23‐25 . Patients have subclinical decreases in a variety of hepatically synthesized proteins, including Apo A1 and ferritin, and hepatic knockout of frataxin is toxic to the liver in mice 25‐27 . Activation of Nrf2 induces aminotransferase genes and serum activity of ALT and AST in some situations.…”

“…[23][24][25] Patients have subclinical decreases in a variety of hepatically synthesized proteins, including Apo A1 and ferritin, and hepatic knockout of frataxin is toxic to the liver in mice. [25][26][27] Activation of Nrf2 induces aminotransferase genes and serum activity of ALT and AST in some situations. Exposure of liver cells to omaveloxolone or its analogue, bardoxolone methyl, results in concentration-dependent increases in both ALT and AST mRNA levels.…”

Plasma multi-omics analysis reveals very long chain ceramides as validated biomarkers of Friedreich’s ataxia

“…7E). A previous report using a stable isotope dilution quantification of APOA1 in FRDA serum samples also observed the decrease of APOA1 37 . Considering the label-free quantification strategy and the smaller number of samples in the validation set a more targeted method with a larger number of samples could help the validation of additional apolipoproteins in plasma similar to the reduced levels of ApoA in FRDA serum 37 .…”

“…Decreased levels of several apolipoproteins from our discovery cohort failed to validate in the validation cohort (8 out 9 could not be validated). By comparing the APOA1 levels between FRDA patients and healthy control in a larger cohort 37 , APOA1 levels were significantly decreased in FRDA serum samples. It appears that a larger cohort is necessary for robust proteomics biomarkers, due to the inherent challenges in measuring plasma proteins.…”

Using biochemistry and biophysics to extinguish androgen receptor signaling in prostate cancer

“…Stable isotope dilution–immunoprecipitation–liquid chromatography–mass spectrometry (SID-IP-LC-MS) offers a new approach to quantifying protein biomarkers ( 124 , 125 ). This methodology has made it possible to rigorously quantify circulating proteins in the plasma ( 126 , 127 ), serum ( 127 , 128 ), and circulating blood cells ( 129 ) with precision and accuracy typical of that attained for drugs and endogenous small molecules. SID-IP-LC-MS can also be used for the quantification of protein splice variants ( 126 ) as well as posttranslationally modified proteins ( 127 ) in the systemic circulation.…”