Hepatocyte-specific activity of TSC22D4 triggers progressive NAFLD by impairing mitochondrial function.
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Authors
Wolff, Gretchen
Sakurai, Minako
Mhamane, Amit
Troullinaki, Maria
Maida, Adriano
Deligiannis, Ioannis K
Yin, Kelvin
Weber, Peter
Morgenstern, Jakob
Wieder, Annika
Kwon, Yun
Sekar, Revathi
Zeigerer, Anja
Roden, Michael
Blüher, Matthias
Volk, Nadine
Poth, Tanja
Hackert, Thilo
Wiedmann, Lena
De Angelis Rigotti, Francesca
Fischer, Andreas
Mukthavaram, Rajesh
Limphong, Pattraranee
Tachikawa, Kiyoshi
Karmali, Priya
Payne, Joseph
Chivukula, Padmanabh
Ekim-Üstünel, Bilgen
Martinez-Jimenez, Celia P
Szendrödi, Julia
Nawroth, Peter
Herzig, Stephan
Publication Date
2022-06Journal Title
Mol Metab
ISSN
2212-8778
Publisher
Elsevier BV
Volume
60
Language
eng
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
Wolff, G., Sakurai, M., Mhamane, A., Troullinaki, M., Maida, A., Deligiannis, I. K., Yin, K., et al. (2022). Hepatocyte-specific activity of TSC22D4 triggers progressive NAFLD by impairing mitochondrial function.. Mol Metab, 60 https://doi.org/10.1016/j.molmet.2022.101487
Abstract
OBJECTIVE: Fibrotic organ responses have recently been identified as long-term complications in diabetes. Indeed, insulin resistance and aberrant hepatic lipid accumulation represent driving features of progressive non-alcoholic fatty liver disease (NAFLD), ranging from simple steatosis and non-alcoholic steatohepatitis (NASH) to fibrosis. Effective pharmacological regimens to stop progressive liver disease are still lacking to-date. METHODS: Based on our previous discovery of transforming growth factor beta-like stimulated clone (TSC)22D4 as a key driver of insulin resistance and glucose intolerance in obesity and type 2 diabetes, we generated a TSC22D4-hepatocyte specific knockout line (TSC22D4-HepaKO) and exposed mice to control or NASH diet models. Mechanistic insights were generated by metabolic phenotyping and single-nuclei RNA sequencing. RESULTS: Hepatic TSC22D4 expression was significantly correlated with markers of liver disease progression and fibrosis in both murine and human livers. Indeed, hepatic TSC22D4 levels were elevated in human NASH patients as well as in several murine NASH models. Specific genetic deletion of TSC22D4 in hepatocytes led to reduced liver lipid accumulation, improvements in steatosis and inflammation scores and decreased apoptosis in mice fed a lipogenic MCD diet. Single-nuclei RNA sequencing revealed a distinct TSC22D4-dependent gene signature identifying an upregulation of mitochondrial-related processes in hepatocytes upon loss of TSC22D4. An enrichment of genes involved in the TCA cycle, mitochondrial organization, and triglyceride metabolism underscored the hepatocyte-protective phenotype and overall decreased liver damage as seen in mouse models of hepatocyte-selective TSC22D4 loss-of-function. CONCLUSIONS: Together, our data uncover a new connection between targeted depletion of TSC22D4 and intrinsic metabolic processes in progressive liver disease. Hepatocyte-specific reduction of TSC22D4 improves hepatic steatosis and promotes hepatocyte survival via mitochondrial-related mechanisms thus paving the way for targeted therapies.
Keywords
fibrosis, NASH, Nafld, Hepatocyte-specific, Tsc22d4
Identifiers
35378329, PMC9034319
External DOI: https://doi.org/10.1016/j.molmet.2022.101487
This record's URL: https://www.repository.cam.ac.uk/handle/1810/336899
Rights
Attribution-NonCommercial-NoDerivatives 4.0 International
Licence URL: https://creativecommons.org/licenses/by-nc-nd/4.0/
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