2. Academic Validation
  3. Liver lipophagy ameliorates nonalcoholic steatohepatitis through extracellular lipid secretion

Liver lipophagy ameliorates nonalcoholic steatohepatitis through extracellular lipid secretion

  • Nat Commun. 2023 Jul 13;14(1):4084. doi: 10.1038/s41467-023-39404-6.
Yoshito Minami # 1,  Atsushi Hoshino # 2,  Yusuke Higuchi 1,  Masahide Hamaguchi 3,  Yusaku Kaneko 1,  Yuhei Kirita 4,  Shunta Taminishi 1,  Toshiyuki Nishiji 1,  Akiyuki Taruno 5 6 7,  Michiaki Fukui 3,  Zoltan Arany 8,  Satoaki Matoba 1
Affiliations

Affiliations

  • 1 Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, 602-8566, Japan.
  • 2 Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, 602-8566, Japan. a-hoshi@koto.kpu-m.ac.jp.
  • 3 Department of Endocrinology and Metabolism, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, 602-8566, Japan.
  • 4 Department of Nephrology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, 602-8566, Japan.
  • 5 Department of Molecular Cell Physiology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, 602-8566, Japan.
  • 6 Japan Science and Technology Agency, PRESTO, Kawaguchi, Saitama, 332-0012, Japan.
  • 7 Japan Science and Technology Agency, CREST, Kawaguchi, Saitama, 332-0012, Japan.
  • 8 Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. zarany@pennmedicine.upenn.edu.
  • # Contributed equally.
PMID: 37443159 DOI: 10.1038/s41467-023-39404-6
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.

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