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- Title
Liver lipophagy ameliorates nonalcoholic steatohepatitis through extracellular lipid secretion.
- Authors
Minami, Yoshito; Hoshino, Atsushi; Higuchi, Yusuke; Hamaguchi, Masahide; Kaneko, Yusaku; Kirita, Yuhei; Taminishi, Shunta; Nishiji, Toshiyuki; Taruno, Akiyuki; Fukui, Michiaki; Arany, Zoltan; Matoba, Satoaki
- 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. Nonalcoholic steatohepatitis (NASH) starts with lipid droplet accumulation in the liver that eventually causes inflammation and fibrosis. Here, authors use lipophagy activators to limit the accumulation of lipids in the liver and show that this can prevent disease progression in a mouse model of nonalcoholic steatohepatitis.
- Subjects
NON-alcoholic fatty liver disease; FREE fatty acids; SYNTHETIC proteins; LIPOLYSIS; ADAPTOR proteins; LIVER; LIPIDS
- Publication
Nature Communications, 2023, Vol 14, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-023-39404-6