RRC ID 76637
Author Minami Y, Hoshino A, Higuchi Y, Hamaguchi M, Kaneko Y, Kirita Y, Taminishi S, Nishiji T, Taruno A, Fukui M, Arany Z, Matoba S.
Title Liver lipophagy ameliorates nonalcoholic steatohepatitis through extracellular lipid secretion.
Journal Nat Commun
Abstract Nonalcoholic steatohepatitis (NASH) is a progressive disorder with aberrant lipid accumulation and subsequent inflammatory and profibrotic response. Therapeutic efforts at lipid reduction via increasing cytoplasmic lipolysis unfortunately worsens hepatitis due to toxicity of liberated fatty acid. An alternative approach could be lipid reduction through autophagic disposal, i.e., lipophagy. We engineered a synthetic adaptor protein to induce lipophagy, combining a lipid droplet-targeting signal with optimized LC3-interacting domain. Activating hepatocyte lipophagy in vivo strongly mitigated both steatosis and hepatitis in a diet-induced mouse NASH model. Mechanistically, activated lipophagy promoted the excretion of lipid from hepatocytes, thereby suppressing harmful intracellular accumulation of nonesterified fatty acid. A high-content compound screen identified alpelisib and digoxin, clinically-approved compounds, as effective activators of lipophagy. Administration of alpelisib or digoxin in vivo strongly inhibited the transition to steatohepatitis. These data thus identify lipophagy as a promising therapeutic approach to prevent NASH progression.
Volume 14(1)
Pages 4084
Published 2023-7-13
DOI 10.1038/s41467-023-39404-6
PII 10.1038/s41467-023-39404-6
PMID 37443159
PMC PMC10344867
MeSH Animals Autophagy Digoxin / pharmacology Fatty Acids / metabolism Hepatitis* Hepatocytes / metabolism Lipid Metabolism Lipids Liver / metabolism Mice Mice, Inbred C57BL Non-alcoholic Fatty Liver Disease* / metabolism
IF 12.121
Mice RBRC02975