RESUMO
Inflammation and oxidative stress are the key factors in the pathogenesis of both metabolic dysfunction-associated steatohepatitis (MASH) and atherosclerosis. Obeticholic acid (OCA), a farnesoid X receptor (FXR) agonist, improves hepatic inflammation and fibrosis in patients with MASH. However, it also reduces HDL cholesterol, suggesting that OCA may increase cardiovascular disease (CVD) risk in patients with MASH. We assessed HDL cholesterol efflux function, antioxidant (paraoxonase and ceruloplasmin activity), pro-inflammatory index, and particle sizes in a small group of patients with and without diabetes (n = 10/group) at baseline and after 18 months of OCA treatment. Patients on lipid-lowering medications (statins, fibrates) were excluded. At baseline, ferritin levels were higher in patients with MASH without diabetes (336.5 [157.0, 451.0] vs. 83 [36.0, 151.0] ng/mL, p < 0.005). Markers of HDL functions were similar in both groups. OCA therapy significantly improved liver histology and liver enzymes but increased alkaline phosphatase levels in nondiabetic patients with MASH (p < 0.05). However, it did not have any significant effect on cholesterol efflux and the antioxidant paraoxonase functions. In nondiabetics, ceruloplasmin (CP) antioxidant activity decreased (p < 0.005) and the pro-inflammatory index of HDL increased (p < 0.005) due to OCA therapy. In contrast, in diabetics, OCA increased levels of pre-ß-HDL-the HDL particles enhanced protective capacity (p = 0.005) with no alteration in HDL functionality. In all patients, serum glucose levels were negatively correlated with OCA-induced change in pro-inflammatory function in HDL (p < 0.001), which was primarily due to diabetes (p = 0.05). These preliminary results suggest a distinct effect of OCA therapy on diabetic and nondiabetic patients with MASH and warrant a future large-scale study.
RESUMO
Propionic acidemia (PA), arising from PCCA or PCCB variants, manifests as life-threatening cardiomyopathy and arrhythmias, with unclear pathophysiology. In this work, propionyl-CoA metabolism in rodent hearts and human pluripotent stem cell-derived cardiomyocytes was investigated with stable isotope tracing analysis. Surprisingly, gut microbiome-derived propionate rather than the propiogenic amino acids (valine, isoleucine, threonine, and methionine) or odd-chain fatty acids was found to be the primary cardiac propionyl-CoA source. In a Pcca-/-(A138T) mouse model and PA patients, accumulated propionyl-CoA and diminished acyl-CoA synthetase short-chain family member 3 impede hepatic propionate disposal, elevating circulating propionate. Prolonged propionate exposure induced significant oxidative stress in PCCA knockdown HL-1 cells and the hearts of Pcca-/-(A138T) mice. Additionally, Pcca-/-(A138T) mice exhibited mild diastolic dysfunction after the propionate challenge. These findings suggest that elevated circulating propionate may cause oxidative damage and functional impairment in the hearts of patients with PA.
RESUMO
Propionic acidemia (PA), resulting from Pcca or Pccb gene mutations, impairs propionyl-CoA metabolism and induces metabolic alterations. While speculation exists that fasting might exacerbate metabolic crises in PA patients by accelerating the breakdown of odd-chain fatty acids and amino acids into propionyl-CoA, direct evidence is lacking. Our investigation into the metabolic effects of fasting in Pcca-/-(A138T) mice, a PA model, reveals surprising outcomes. Propionylcarnitine, a PA biomarker, decreases during fasting, along with the C3/C2 (propionylcarnitine/acetylcarnitine) ratio, ammonia, and methylcitrate. Although moderate amino acid catabolism to propionyl-CoA occurs with a 23-h fasting, a significant reduction in microbiome-produced propionate and increased fatty acid oxidation mitigate metabolic alterations by decreasing propionyl-CoA synthesis and enhancing acetyl-CoA synthesis. Fasting-induced gluconeogenesis further facilitates propionyl-CoA catabolism without changing propionyl-CoA carboxylase activity. These findings suggest that fasting may alleviate metabolic alterations in Pcca-/-(A138T) mice, prompting the need for clinical evaluation of its potential impact on PA patients.