Hepatic HKDC1 Deletion Alleviates Western Diet-Induced MASH in Mice
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Abstract
The global prevalence of Metabolic dysfunction-associated steatohepatitis (MASH) has been rising sharply, closely mirroring the increasing rates of obesity and metabolic syndrome. MASH exhibits a strong sexual dimorphism where females are affected with more severe forms after menopause. Hexokinase domain-containing protein 1 (HKDC1) has recently been recognized for its role in liver diseases, where its expression is minimal under normal conditions but significantly increases in response to metabolic stressors like obesity and liver injury. This selective upregulation suggests HKDC1’s potential specialization in hepatic glucose and lipid dysregulation, linking it closely to the progression of MASLD and MASH. This study aims to clarify the role of HKDC1 in Western diet-induced MASH in female mice by examining its impact on hepatic glucose and lipid metabolism, offering insights into its potential as a therapeutic target and addressing the need for sex-specific research in liver disease. This study reveals that HKDC1 expression is elevated in obese women with MASH and correlates with liver pathology. In a mouse model, liver-specific HKDC1 knockout (HKDC1 LKO ) protected against Western diet-induced obesity, glucose intolerance, and MASH features, including steatosis, inflammation, and fibrosis. Transcriptomic analysis showed that HKDC1 deletion reduced pro-inflammatory and pro-fibrotic gene expression, while gut microbiome analysis indicated a shift toward MASH-protective bacteria. These findings suggest that HKDC1 may exacerbate MASH progression through its role in metabolic and inflammatory pathways, making it a potential therapeutic target.
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In summary, the gut microbiome of HKDC1 liver-specific knockout mice has fewer bacterial strains that positively correlate with MASH, which may partially contribute to or result from the improved phenotype of mice with hepatic HKDC1 ablation.
Very interesting that HKDC1 KO reduces uptake of lipids from the gut. Are you able to experimentally determine whether there is a link between changes in microbiome composition and lipid update? How would you do this?
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Gene ontology analysis of the downregulated genes revealed that the “extracellular matrix organization” pathway is the most affected pathway (Figure 7C). A further in-depth analysis of this pathway revealed that most of the genes belonged to the pro-fibrogenic program (Fig 7D)
How does HKDC1 ablation reduce fibrotic signaling?
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a possible mechanism by which HKDC1 upregulation exacerbates MASH development is through dysregulating cholesterol metabolism.
Do you have a hypothesis as to how HKDC1 contributes to dysregulated cholesterol metabolism?
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More importantly, HKDC1 levels were not only significantly upregulated in differentiated HLO with respect to undifferentiated HLO but were also increased after PA treatment (Fig 1H), suggesting that a high lipid environment can regulate HKDC1 expression.
Why does treatment with albumin also lead to upregulation of HKDC1 in your organoid experiment?
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