Poster Topical Area: Carotenoids and Retinoids

Location: Auditorium

Poster Board Number: 9

P03-001 - Hepatic Stellate Cells Exposed to Astaxanthin During Activation Exhibit a Distinct Metabotype from Quiescent and Activated Hepatic Stellate Cells

Sunday, Jun 10
8:00 AM – 6:00 PM

Objectives: Hepatic stellate cells (HSCs) are responsible for the excess accumulation of extracellular matrix, leading to liver fibrosis. We demonstrated that activated HSCs (aHSCs) had higher mitochondrial respiration and lower glycolysis than quiescent HSCs (qHSCs), and the changes were attenuated by astaxanthin (ASTX). The objective of this study was to determine the underlying mechanisms by which qHSCs and aHSCs display distinct metabotypes and how ASTX alters the changes.

Primary mouse HSCs were cultured on an uncoated plastic dish for activation. The cells at day 1 and day 7 served as qHSCs and aHSCs, respectively, and sets of cells were treated with 25 μM of ASTX in the presence/absence of FCCP, an uncoupler, during activation. Mitochondrial contents and cristae structure (by transmission electron microscopy), and the expression of genes for mitochondrial biogenesis were measured. The followings were also measured to understand the modulation of glycolysis during HSC activation: mRNA levels of genes for glycolysis, such as glucose transporter 1 (Glut1), lactate dehydrogenase A (Ldha), and monocarboxylate transporter 1 (Mct1); phosphorylation of pyruvate dehydrogenase (PDH); and lactate secretion.

aHSCs had higher mitochondrial contents and expression of proliferator-activated receptor γ coactivator 1β than qHSCs. Inhibition of mitochondrial respiration by FCCP markedly reduced pro-fibrogenic gene expression in aHSCs, which was further reduced by ASTX. ASTX also improved mitochondrial cristae structure with decreased cristae junction width, lumen width, and area. As for glycolysis, aHSCs showed lower mRNA and protein levels of GLUT1, but higher protein levels of phosphorylated PDH than qHSCs, suggesting that aHSCs are likely to have diminished cellular glucose uptake and conversion of pyruvate to acetyl-CoA. ASTX increased lactate secretion with concomitant increases in the expression of Ldha and Mct1.

qHSCs showed a glycolytic metabotype while aHSCs had an oxidative metabotype. aHSCs treated with ASTX exhibited a distinct metabotype from qHSCs and aHSCs with increased glycolysis and decreased mitochondrial respiration. Metabotypic changes in HSCs may be a great target for the prevention of liver fibrosis.

Funding Source: NIH 1R01DK108254-01

CoAuthors: Tho Pham – University of Connecticut; Young-Ki Park – University of Connecticut; Yoojin Lee – University of Connecticut; Siqi Hu – University of Connecticut; Dong-Guk Shin – University of Connecticut; Pujan Joshi – University of Connecticut; Seung-Hyun Hong – University of Connecticut; Nathan Alder – University of Connecticut; Sung Koo – University of Connecticut; Ji-Young Lee – University of Connecticut

Minkyung Bae

Graduate Student
University of Connecticut
Storrs, Connecticut