T1620 Loss of Mitochondrial Content and Function Contribute to the Natural History of Nonalcoholic Fatty Liver Disease in a Hyperphagic Obese Rodent Model

Rector, Scott; Thyfault, John P.; Uptergrove, Grace M.; Morris, E. Matthew; Naples, Scott P.; Borengasser, Sarah J.; Mikus, Catherine R.; Laye, Matthew J.; Laughlin, M. Harold; Booth, Frank W.; Ibdah, Jamal A.

doi:10.1016/s0016-5085(09)63920-2

Cited by 5 publications

(5 citation statements)

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“…In addition, some data suggest mitochondrial dysregulation to be an initial step in the pathway to insulin resistance and hepatic steatosis by highlighting the role of mitochondrial complexes in obesity and progression to NAFLD [38][39][40]. While others have demonstrated deficits in specific complex subunit proteins such as Ndufa 9 [41] Ndufa (1,2,11), Ndufb (6,7,9) in progressive NAFLD and NASH [42].…”

Section: Discussionmentioning

confidence: 99%

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

Wolff

Sakurai

Mhamane

et al. 2021

Preprint

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Objective: Fibrotic organ responses have recently been identified as long-term complication 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 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 cell liver 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. Single cell RNA sequencing revealed a distinct gene signature identifying an upregulation of mitochondrial-related processes. 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. Conclusions: Together, our data uncover a new connection between targeted depletion of TSC22D4 and intrinsic metabolic processes in progressive liver disease. Cell-specific reduction of TSC22D4 improves hepatic steatosis, inflammation and promotes hepatocyte survival thus paving the way for further preclinical therapy developments.

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Section: Discussionmentioning

confidence: 99%

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

Wolff

Sakurai

Mhamane

et al. 2021

Preprint

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“…(Brownlow et al 1996.) However, as several recent studies have demonstrated, many pathological metabolic events associated with chronic diseases may be prevented or delayed when physical activity is commenced (Linden et al 2013;Rector et al 2010;Laye 2009;Lakka & Laaksonen 2007). Physical activity is defined by the Centers for Disease Control and Prevention (CDC) as "any bodily movement produced by the contraction of skeletal muscle that increases energy expenditure above a basal level.…”

Section: Physical Activitymentioning

confidence: 99%

Lipid droplet-associated proteins in high-fat fed mice with the effects of voluntary running and diet change

et al. 2014

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“…Iron is a catalyst for the production of reactive oxygen species (ROS), which may initiate oxidative stress and cellular lipid peroxidation (4). Oxidative stress often leads to mitochondrial dysfunction, a precursor of impaired fatty acid (FA) oxidation and subsequent development of steatosis (28). Excess iron, therefore, may play a causal role in the development of steatosis (33).…”

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confidence: 99%

Altered lipid metabolism in Hfe-knockout mice promotes severe NAFLD and early fibrosis

Tan

Crawford

Jaskowski

et al. 2011

American Journal of Physiology-Gastrointestinal and Liver Physi

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Tan TC, Crawford DH, Jaskowski LA, Murphy TM, Heritage ML, Subramaniam VN, Clouston AD, Anderson GJ, Fletcher LM. Altered lipid metabolism in Hfe-knockout mice promotes severe NAFLD and early fibrosis. Am J Physiol Gastrointest Liver Physiol 301: G865-G876, 2011. First published August 4, 2011; doi:10.1152/ajpgi.00150.2011.-The HFE protein plays a crucial role in the control of cellular iron homeostasis. Steatosis is commonly observed in HFE-related iron-overload disorders, and current evidence suggests a causal link between iron and steatosis. Here, we investigated the potential contribution of HFE mutations to hepatic lipid metabolism and its role in the pathogenesis of nonalcoholic fatty liver disease. Wild-type (WT) and Hfe knockout mice (Hfe Ϫ/Ϫ ) were fed either standard chow, a monounsaturated low fat, or a high-fat, high-carbohydrate diet (HFD) and assessed for liver injury, body iron status, and markers of lipid metabolism. Despite hepatic iron concentrations and body weights similar to WT controls, Hfe Ϫ/Ϫ mice fed the HFD developed severe hypoxia-related steatohepatitis, Tnf-␣ activation, and mitochondrial respiratory complex and antioxidant dysfunction with early fibrogenesis. These features were associated with an upregulation in the expression of genes involved in intracellular lipid synthesis and trafficking, while transcripts for mitochondrial fatty acid ␤-oxidation and adiponectin signaling-related genes were significantly attenuated. In contrast, HFD-fed WT mice developed bland steatosis only, with no inflammation or fibrosis and no upregulation of lipogenesis-related genes. A HFD led to reduced hepatic iron in Hfe Ϫ/Ϫ mice compared with chow-fed mice, despite higher serum iron, decreased hepcidin expression, and increased duodenal ferroportin mRNA. In conclusion, our results demonstrate that Hfe Ϫ/Ϫ mice show defective hepatic-intestinal iron and lipid signaling, which predispose them toward diet-induced hepatic lipotoxicity, accompanied by an accelerated progression of injury to fibrosis.

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T1620 Loss of Mitochondrial Content and Function Contribute to the Natural History of Nonalcoholic Fatty Liver Disease in a Hyperphagic Obese Rodent Model

Cited by 5 publications

References 0 publications

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

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

Lipid droplet-associated proteins in high-fat fed mice with the effects of voluntary running and diet change

Altered lipid metabolism in Hfe-knockout mice promotes severe NAFLD and early fibrosis

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