Browsing by Author "Lai, Michelle"

Now showing 1 - 2 of 2
  • Thumbnail Image
    Item
    Lipoprotein Z, a hepatotoxic lipoprotein, predicts outcome in alcohol-associated hepatitis
    (Wiley, 2022) Hu, Kunpeng; Perez-Matos, Maria C.; Argemi, Josepmaria; Vilar-Gomez, Eduardo; Shalaurova, Irina; Bullitt, Esther; Landeen, Lee; Sugahara, Go; Deng, Huiyan; Mathur, Karan; Tran, Stephanie; Cai, Huimei; He, Hanchang; Yalcin, Yusuf; Barbosa, Joana Vieira; Ventura-Cots, Meritxell; Marx, Katherine; Gad, Aniket P.; Niezen, Sebastian; Barba, Sofia Izunza; Ang, Lay-Hong; Popov, Yury V.; Fricker, Zachary; Lai, Michelle; Curry, Michael; Afdhal, Nezam; Szabo, Gyongyi; Mukamal, Kenneth J.; Sanyal, Arun J.; Otvos, James D.; Malik, Raza; Saito, Takeshi; Connelly, Margery A.; Chalasani, Naga P.; Bataller, Ramon; Jiang, Z. Gordon; Medicine, School of Medicine
    Background and aims: Lipoprotein Z (LP-Z) is an abnormal free cholesterol (FC)-enriched LDL-like particle discovered from patients with cholestatic liver disease. This study aims to define the diagnostic value of LP-Z in alcohol-associated hepatitis (AH) and interrogate the biology behind its formation. Approach and results: We measured serum levels of LP-Z using nuclear magnetic resonance spectroscopy, a well-established clinical assay. Serum levels of LP-Z were significantly elevated in four AH cohorts compared with control groups, including heavy drinkers and patients with cirrhosis. We defined a Z-index, calculated by the ratio of LP-Z to total apolipoprotein B-containing lipoproteins, representing the degree of deviation from normal VLDL metabolism. A high Z-index was associated with 90-day mortality independent from the Model for End-Stage Liver Disease (MELD) and provided added prognosticative value. Both a Z-index ≤ 0.6 and a decline of Z-index by ≥0.1 in 2 weeks predicted 90-day survival. RNA-sequencing analyses of liver tissues demonstrated an inverse association in the expression of enzymes responsible for the extrahepatic conversion of VLDL to LDL and AH disease severity, which was further confirmed by the measurement of serum enzyme activity. To evaluate whether the FC in LP-Z could contribute to the pathogenesis of AH, we found significantly altered FC levels in liver explant of patients with AH. Furthermore, FC in reconstituted LP-Z particles caused direct toxicity to human hepatocytes in a concentration-dependent manner, supporting a pathogenic role of FC in LP-Z. Conclusions: Impaired lipoprotein metabolism in AH leads to the accumulation of LP-Z in the circulation, which is hepatotoxic from excessive FC. A Z-index ≤ 0.6 predicts 90-day survival independent from conventional biomarkers for disease prognostication.
  • Thumbnail Image
    Item
    Saroglitazar, a PPAR-α/γ Agonist, for Treatment of Nonalcoholic Fatty Liver Disease: A Randomized Controlled Double-Blind Phase 2 Trial
    (Wiley, 2021-10) Gawrieh, Samer; Noureddin, Mazen; Loo, Nicole; Mohseni, Rizwana; Awasty, Vivek; Cusi, Kenneth; Kowdley, Kris V.; Lai, Michelle; Schiff, Eugene; Parmar, Deven; Patel, Pankaj; Chalasani, Naga; Medicine, School of Medicine
    Background and Aims Non-alcoholic fatty liver disease (NAFLD) is characterized by insulin resistance and dysregulated lipid and glucose metabolism. Saroglitazar, a novel dual peroxisome proliferator activated receptor-α/γ agonist, improves insulin sensitivity, and lipid and glycemic parameters. Saroglitazar improved nonalcoholic steatohepatitis (NASH) histology in animal studies. In this randomized controlled clinical trial, we evaluated the efficacy and safety of saroglitazar in patients with NAFLD/NASH. Approach & Results A total of 106 patients with NAFLD/NASH with ALT ≥50 U/L at baseline and body mass index ≥25 kg/m2 were randomized in a 1:1:1:1 ratio to receive placebo or saroglitazar 1 mg, 2 mg, or 4 mg for 16 weeks. The primary efficacy endpoint was percentage change from baseline in ALT levels at Week 16. Liver fat content (LFC) was assessed by magnetic resonance imaging-proton density fat fraction. The least squares (LS) mean (SE) percent change from baseline in ALT at Week 16 was -25.5% (5.8), -27.7% (5.9) and -45.8% (5.7) with saroglitazar 1 mg, 2 mg, and 4 mg, respectively versus 3.4% (5.6) in placebo (p<0.001 for all). Compared to placebo, saroglitazar 4 mg improved LFC [4.1%, (5.9) versus -19.7% (5.6)], adiponectin [-0.3 ug/mL (0.3) versus 1.3 ug/mL (0.3)], homeostatic model assessment-insulin resistance [-1.3 (1.8) versus -6.3 (1.7)], and triglycerides [-5.3 mg/dL (10.7) versus -68.7 mg/dL (10.3)] (p<0.05 for all). Saroglitazar 4 mg also improved lipoprotein particle composition and size and reduced lipotoxic lipid species. Saroglitazar was well-tolerated. A mean weight gain of 1.5kg was observed with saroglitazar 4 mg versus 0.3 kg with placebo (p>0.05). Conclusions Saroglitazar 4 mg significantly improved ALT, LFC, insulin resistance and atherogenic dyslipidemia in participants with NAFLD/NASH.