| 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
|
| Resource |
| Mice |
RBRC02975 |
