Hepatocyte-specific activity of TSC22D4 triggers progressive NAFLD by impairing mitochondrial function

Wolff, Gretchen; Sakurai, Minako; Mhamane, Amit; Troullinaki, Maria; Maida, Adriano; Deligiannis, Ioannis K; Yin, Kai; Weber, Peter; Morgenstern, Jakob; Wieder, Annika; Kwon, Yongseok; Sekar, Revathi; Zeigerer, Anja; Roden, Michael; Blüher, Matthias; Volk, Nadine; Poth, Tanja; Hackert, Thilo; Wiedmann, Lena; Rigotti, Francesca; Rodríguez-Vita, Juan; Fischer, Andreas; Mukthavaram, Rajesh; Limphong, Pattraranee; Karmali, Priya; Payne, Joseph E.; Chivukula, Padmanabh; Ekim-Üstünel, Bilgen; Martínez-Jiménez, Celia P.; Szendrödi, Julia; Nawroth, Peter P.; Herzig, Stephan

doi:10.1016/j.molmet.2022.101487

Cited by 5 publications

(5 citation statements)

References 46 publications

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“…Next, we checked the liver lipid levels in mice expressing different TSC22D4 alleles. In agreement with our recent findings ( 25 ), hepatic overexpression of WT-TSC22D4, but not the D2 + TSC mutant, tended to elevate liver triglycerides upon 7 weeks of HF/HS diet (fig. S7A).…”

Section: Resultssupporting

confidence: 93%

“…S2, B and C). TSC22D4 remained mainly cytoplasmic, whereas Akt1 presented both cytoplasmic and nuclear localization in agreement with previously published studies ( 23 – 25 ).…”

Section: Resultssupporting

confidence: 93%

“…To avoid potential interference from the endogenous TSC22D4 that would exist in WT mice, we used hepatocyte-specific TSC22D4 KO (TSC22D4 hep−/− ) mice for introduction of TSC22D4 alleles (fig. S5E) ( 25 ). Similar to our previous findings ( 7 ), TSC22D4 hep−/− mice had improved glucose handling in glucose tolerance test (GTT) and lower fasting blood glucose levels compared to TSC22D4 flox/flox control mice when challenged with high-fat diet (HFD) without any changes in body weight (fig.…”

Section: Resultsmentioning

confidence: 99%

“…Male albumin-cre mice crossed to the TSC22D4 floxed/floxed (TSC22D4 flox/flox ) line (C57Bl/6N background) ( 25 ) were housed at room temperature (RT) with 12-hour light–12-hour dark cycle on control diet (Research Diets, New Brunswick, NJ, USA; D12450B), 60% HFD (Research Diets, D12492i) with sucrose-containing drinking water (42 g/liter), or chow diet (10% energy from fat; Research Diets, D12450Ji) for weeks indicated for each study. Mice had ad libitum access to food and water and were weighed regularly and inspected daily for general health.…”

Section: Methodsmentioning

confidence: 99%

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TSC22D4 interacts with Akt1 to regulate glucose metabolism

et al. 2022

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Maladaptive insulin signaling is a key feature in the pathogenesis of severe metabolic disorders, including obesity and diabetes. Enhancing insulin sensitivity represents a major goal in the treatment of patients affected by diabetes. Here, we identify transforming growth factor–β1 stimulated clone 22 D4 (TSC22D4) as a novel interaction partner for protein kinase B/Akt1, a critical mediator of insulin/phosphatidylinositol 3-kinase signaling pathway. While energy deprivation and oxidative stress promote the TSC22D4-Akt1 interaction, refeeding mice or exposing cells to glucose and insulin impairs this interaction, which relies on an intrinsically disordered region (D2 domain) within TSC22D4. Functionally, the interaction with TSC22D4 reduces basal phosphorylation of Akt and its downstream targets during starvation, thereby promoting insulin sensitivity. Genetic, liver-specific reconstitution experiments in mice demonstrate that the interaction between TSC22D4 and Akt1 improves glucose handling and insulin sensitivity. Overall, our findings postulate a model whereby TSC22D4 acts as an environmental sensor and interacts with Akt1 to regulate insulin signaling and glucose metabolism.

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Section: Resultssupporting

confidence: 93%

“…S2, B and C). TSC22D4 remained mainly cytoplasmic, whereas Akt1 presented both cytoplasmic and nuclear localization in agreement with previously published studies ( 23 – 25 ).…”

Section: Resultssupporting

confidence: 93%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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TSC22D4 interacts with Akt1 to regulate glucose metabolism

et al. 2022

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“…This culminates in a vicious cycle in which massive ROS production exacerbates apoptosis. Although a link between apoptosis stimulated by mitochondrial dysfunction and MASLD has been proposed [ 77 , 78 ], further research is necessitated to determine the mechanisms by which SFA regulates mitochondrial respiration, electron leakage, and other pathways that may play a role in the initiation of apoptotic processes.…”

Section: Lipotoxicity In Masldmentioning

confidence: 99%

Updated mechanisms of MASLD pathogenesis

Li,

Yang,

et al. 2024

Lipids Health Dis

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Metabolic dysfunction-associated steatotic liver disease (MASLD) has garnered considerable attention globally. Changing lifestyles, over-nutrition, and physical inactivity have promoted its development. MASLD is typically accompanied by obesity and is strongly linked to metabolic syndromes. Given that MASLD prevalence is on the rise, there is an urgent need to elucidate its pathogenesis. Hepatic lipid accumulation generally triggers lipotoxicity and induces MASLD or progress to metabolic dysfunction-associated steatohepatitis (MASH) by mediating endoplasmic reticulum stress, oxidative stress, organelle dysfunction, and ferroptosis. Recently, significant attention has been directed towards exploring the role of gut microbial dysbiosis in the development of MASLD, offering a novel therapeutic target for MASLD. Considering that there are no recognized pharmacological therapies due to the diversity of mechanisms involved in MASLD and the difficulty associated with undertaking clinical trials, potential targets in MASLD remain elusive. Thus, this article aimed to summarize and evaluate the prominent roles of lipotoxicity, ferroptosis, and gut microbes in the development of MASLD and the mechanisms underlying their effects. Furthermore, existing advances and challenges in the treatment of MASLD were outlined.

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