Liver lipophagy ameliorates nonalcoholic steatohepatitis through extracellular lipid secretion

Yoshito Minami, Atsushi Hoshino (), Yusuke Higuchi, Masahide Hamaguchi, Yusaku Kaneko, Yuhei Kirita, Shunta Taminishi, Toshiyuki Nishiji, Akiyuki Taruno, Michiaki Fukui, Zoltan Arany () and Satoaki Matoba
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Yoshito Minami: Kyoto Prefectural University of Medicine
Atsushi Hoshino: Kyoto Prefectural University of Medicine
Yusuke Higuchi: Kyoto Prefectural University of Medicine
Masahide Hamaguchi: Kyoto Prefectural University of Medicine
Yusaku Kaneko: Kyoto Prefectural University of Medicine
Yuhei Kirita: Kyoto Prefectural University of Medicine
Shunta Taminishi: Kyoto Prefectural University of Medicine
Toshiyuki Nishiji: Kyoto Prefectural University of Medicine
Akiyuki Taruno: Kyoto Prefectural University of Medicine
Michiaki Fukui: Kyoto Prefectural University of Medicine
Zoltan Arany: University of Pennsylvania
Satoaki Matoba: Kyoto Prefectural University of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-39404-6

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