Cover Story Current Issue
Glucose is a ubiquitous and essential source of energy for all living organisms. Although mammals have evolved ways to convert other nutritional molecules to ATP, the preference for dietary glucose appears to be preserved. In rodents, the immediate detection of ingested glucose potently reinforces intake, hierarchically organizing behaviors towards glucose-yielding substances, and away from other types of food including other sugars. Taste is the primary sense linked to nutrient selection. Until recently, it was thought that most mammalian species utilize a single broadly tuned receptor to detect all simple sugars. Indeed, this “sweet” receptor, which comprises a heterodimer of the T1R2 and T1R3 proteins, binds multiple natural sugars (e.g., glucose, fructose, sucrose, maltose), as well as various other chemicals that yield little to no energy (e.g., low calorie sweeteners, sugar alcohols) and some d-amino acids. The neural signal originating from the sweet receptor is hardwired into brain circuits that drive eating and drinking behaviors, but it is an unreliable indicator of nutrient quality and quantity.
Current Issue
Hepatic stellate cell-specific Kcnma1 deletion mitigates metabolic dysfunction-associated steatotic liver disease progression via upregulating Amphiregulin secretion
Hepatic stellate cell-specific Kcnma1 deletion mitigates metabolic dysfunction-associated steatotic liver disease progression via upregulating Amphiregulin secretion
Objective
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing global health concern, with limited effective treatments. KCNMA1 potassium channel has been implicated in the pathogenesis of various metabolic diseases. However, whether and how KCNMA1 regulates MASLD have been elusive.
Methods
Global, hepatic stellate cells (HSCs)-specific, and hepatocyte-specific Kcnma1 knockout mice were fed either a standard chow or a high-fat diet (HFD). Serum and liver tissues were collected and analyzed by biochemical assay, histology, qPCR and western blotting. HSCs conditioned medium (CM) treatment hepatocytes experiment model and three-dimensional (3D) hepatocytes-HSCs spheroids were employed to study lipid accumulation in hepatocytes. A Cytokine Antibody Array was used to analyze the cytokine profile.
Results
Our study demonstrated that global Kcnma1 deletion prevented diet-induced hepatic steatosis and improved insulin sensitivity. Further analyses using HSC-specific and hepatocyte-specific Kcnma1 knockout MASLD mouse models revealed that the protective effect against hepatic steatosis was predominantly mediated by Kcnma1 deletion in HSCs, rather than in hepatocytes. CM transfer experiment and 3D spheroid studies show Kcnma1 deletion effectively prevents lipid accumulation in hepatocytes. Mechanically, Kcnma1-deficient HSCs secrete Amphiregulin (AREG) to regulate lipid metabolism in hepatocytes via epidermal growth factor receptor (EGFR) signaling. Of clinical significance, AREG levels were notably reduced in the liver tissue of MASLD patients, while injection of recombinant AREG protein significantly ameliorated MASLD in mice.
Conclusions
Our study uncovers a novel mechanism in which Kcnma1 deletion in HSCs enhances AREG secretion, thereby reducing lipid accumulation in hepatocytes through the AREG/EGFR signaling, ultimately inhibiting the progression of MASLD.
Articles in Press
Hepatic stellate cell-specific Kcnma1 deletion mitigates metabolic dysfunction-associated steatotic liver disease progression via upregulating Amphiregulin secretion
Hepatic stellate cell-specific Kcnma1 deletion mitigates metabolic dysfunction-associated steatotic liver disease progression via upregulating Amphiregulin secretion
Objective
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing global health concern, with limited effective treatments. KCNMA1 potassium channel has been implicated in the pathogenesis of various metabolic diseases. However, whether and how KCNMA1 regulates MASLD have been elusive.
Methods
Global, hepatic stellate cells (HSCs)-specific, and hepatocyte-specific Kcnma1 knockout mice were fed either a standard chow or a high-fat diet (HFD). Serum and liver tissues were collected and analyzed by biochemical assay, histology, qPCR and western blotting. HSCs conditioned medium (CM) treatment hepatocytes experiment model and three-dimensional (3D) hepatocytes-HSCs spheroids were employed to study lipid accumulation in hepatocytes. A Cytokine Antibody Array was used to analyze the cytokine profile.
Results
Our study demonstrated that global Kcnma1 deletion prevented diet-induced hepatic steatosis and improved insulin sensitivity. Further analyses using HSC-specific and hepatocyte-specific Kcnma1 knockout MASLD mouse models revealed that the protective effect against hepatic steatosis was predominantly mediated by Kcnma1 deletion in HSCs, rather than in hepatocytes. CM transfer experiment and 3D spheroid studies show Kcnma1 deletion effectively prevents lipid accumulation in hepatocytes. Mechanically, Kcnma1-deficient HSCs secrete Amphiregulin (AREG) to regulate lipid metabolism in hepatocytes via epidermal growth factor receptor (EGFR) signaling. Of clinical significance, AREG levels were notably reduced in the liver tissue of MASLD patients, while injection of recombinant AREG protein significantly ameliorated MASLD in mice.
Conclusions
Our study uncovers a novel mechanism in which Kcnma1 deletion in HSCs enhances AREG secretion, thereby reducing lipid accumulation in hepatocytes through the AREG/EGFR signaling, ultimately inhibiting the progression of MASLD.
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2024 impact factor: 6.6
You are what you eat
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