TY - JOUR
T1 - A structurally engineered fatty acid, icosabutate, suppresses liver inflammation and fibrosis in NASH
AU - Fraser, David A.
AU - Wang, Xiaoyu
AU - Lund, Jenny
AU - Nikolić, Nataša
AU - Iruarrizaga-Lejarreta, Marta
AU - Skjaeret, Tore
AU - Alonso, Cristina
AU - Kastelein, John J. P.
AU - Rustan, Arild C.
AU - Kim, Yong Ook
AU - Schuppan, Detlef
N1 - Funding Information: DS receives project-related support from the German Research Foundation (DFG) Collaborative Research Center (CRC) grants SFB 1066 project B3 and CRC 1292 project B8, and by EU Horizon 2020 projects under grant agreements nr. 634413 (EPoS, European Project on Steatohepatitis) and nr. 777377 (LITMUS, Liver Investigation on Marker Utility in Steatohepatitis). Funding Information: DS receives project-related support from the German Research Foundation (DFG) Collaborative Research Center (CRC) grants SFB 1066 project B3 and CRC 1292 project B8, and by EU Horizon 2020 projects under grant agreements nr. 634413 (EPoS, European Project on Steatohepatitis) and nr. 777377 (LITMUS, Liver Investigation on Marker Utility in Steatohepatitis). Publisher Copyright: © 2021
PY - 2022/4
Y1 - 2022/4
N2 - Background & Aims: Although long-chain omega-3 fatty acids (LCn-3FAs) regulate inflammatory pathways of relevance to non-alcoholic steatohepatitis (NASH), their susceptibility to peroxidation may limit their therapeutic potential. We compared the metabolism of eicosapentaenoic acid (EPA) with an engineered EPA derivative (icosabutate) in human hepatocytes in vitro and their effects on hepatic glutathione metabolism, oxidised lipids, inflammation, and fibrosis in a dietary mouse model of NASH, and in patients prone to fatty liver disease. Methods: Oxidation rates and cellular partitioning of EPA and icosabutate were compared in primary human hepatocytes. Comparative effects of delayed treatment with either low- (56 mg/kg) or high-dose (112 mg/kg) icosabutate were compared with EPA (91 mg/kg) or a glucagon-like peptide 1 receptor agonist in a choline-deficient (CD), L-amino acid-defined NASH mouse model. To assess the translational potential of these findings, effects on elevated liver enzymes and fibrosis-4 (FIB-4) score were assessed in overweight, hyperlipidaemic patients at an increased risk of NASH. Results: In contrast to EPA, icosabutate resisted oxidation and incorporation into hepatocytes. Icosabutate also reduced inflammation and fibrosis in conjunction with a reversal of CD diet-induced changes in the hepatic lipidome. EPA had minimal effect on any parameter and even worsened fibrosis in association with depletion of hepatic glutathione. In dyslipidaemic patients at risk of NASH, icosabutate rapidly normalised elevated plasma ALT, GGT and AST and reduced FIB-4 in patients with elevated ALT and/or AST. Conclusion: Icosabutate does not accumulate in hepatocytes and confers beneficial effects on hepatic oxidative stress, inflammation and fibrosis in mice. In conjunction with reductions in markers of liver injury in hyperlipidaemic patients, these findings suggest that structural engineering of LCn-3FAs offers a novel approach for the treatment of NASH. Lay summary: Long-chain omega-3 fatty acids are involved in multiple pathways regulating hepatic inflammation and fibrosis, but their susceptibility to peroxidation and use as an energy source may limit their clinical efficacy. Herein, we show that a structurally modified omega-3 fatty acid, icosabutate, overcame these challenges and had markedly improved antifibrotic efficacy in a mouse model of non-alcoholic steatohepatitis. A hepatoprotective effect of icosabutate was also observed in patients with elevated circulating lipids, in whom it led to rapid reductions in markers of liver injury.
AB - Background & Aims: Although long-chain omega-3 fatty acids (LCn-3FAs) regulate inflammatory pathways of relevance to non-alcoholic steatohepatitis (NASH), their susceptibility to peroxidation may limit their therapeutic potential. We compared the metabolism of eicosapentaenoic acid (EPA) with an engineered EPA derivative (icosabutate) in human hepatocytes in vitro and their effects on hepatic glutathione metabolism, oxidised lipids, inflammation, and fibrosis in a dietary mouse model of NASH, and in patients prone to fatty liver disease. Methods: Oxidation rates and cellular partitioning of EPA and icosabutate were compared in primary human hepatocytes. Comparative effects of delayed treatment with either low- (56 mg/kg) or high-dose (112 mg/kg) icosabutate were compared with EPA (91 mg/kg) or a glucagon-like peptide 1 receptor agonist in a choline-deficient (CD), L-amino acid-defined NASH mouse model. To assess the translational potential of these findings, effects on elevated liver enzymes and fibrosis-4 (FIB-4) score were assessed in overweight, hyperlipidaemic patients at an increased risk of NASH. Results: In contrast to EPA, icosabutate resisted oxidation and incorporation into hepatocytes. Icosabutate also reduced inflammation and fibrosis in conjunction with a reversal of CD diet-induced changes in the hepatic lipidome. EPA had minimal effect on any parameter and even worsened fibrosis in association with depletion of hepatic glutathione. In dyslipidaemic patients at risk of NASH, icosabutate rapidly normalised elevated plasma ALT, GGT and AST and reduced FIB-4 in patients with elevated ALT and/or AST. Conclusion: Icosabutate does not accumulate in hepatocytes and confers beneficial effects on hepatic oxidative stress, inflammation and fibrosis in mice. In conjunction with reductions in markers of liver injury in hyperlipidaemic patients, these findings suggest that structural engineering of LCn-3FAs offers a novel approach for the treatment of NASH. Lay summary: Long-chain omega-3 fatty acids are involved in multiple pathways regulating hepatic inflammation and fibrosis, but their susceptibility to peroxidation and use as an energy source may limit their clinical efficacy. Herein, we show that a structurally modified omega-3 fatty acid, icosabutate, overcame these challenges and had markedly improved antifibrotic efficacy in a mouse model of non-alcoholic steatohepatitis. A hepatoprotective effect of icosabutate was also observed in patients with elevated circulating lipids, in whom it led to rapid reductions in markers of liver injury.
KW - ALT
KW - FIB-4
KW - antifibrotic
KW - collagen
KW - glutathione
KW - icosabutate
KW - omega-3 fatty acid
KW - oxidative stress
KW - steatohepatitis
UR - http://www.scopus.com/inward/record.url?scp=85124566751&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.jhep.2021.12.004
DO - https://doi.org/10.1016/j.jhep.2021.12.004
M3 - Article
C2 - 34915054
SN - 0168-8278
VL - 76
SP - 800
EP - 811
JO - Journal of Hepatology
JF - Journal of Hepatology
IS - 4
ER -