Calcium Signaling in Liver Metabolism Disorders

Calcium ions act as versatile second messengers in hepatocytes, governing lipid synthesis, carbohydrate metabolism and bile secretion. Under physiological conditions, tightly regulated fluxes of Ca2+ between the endoplasmic reticulum (ER), cytosol and mitochondria ensure optimal energy production and low oxidative stress. Key junctions at mitochondria-associated membranes (MAMs) coordinate ER Ca2+ release through inositol trisphosphate receptors and subsequent mitochondrial uptake to drive ATP synthesis. Pumps such as the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) restore ER stores, while store-operated calcium entry (SOCE) pathways replenish cytosolic Ca2+ after depletion. In metabolic disorders, impaired SERCA activity, aberrant SOCE and prolonged ER stress lead to mitochondrial dysfunction, lipid accumulation and chronic inflammation. These disturbances underpin non-alcoholic fatty liver disease (NAFLD), its progressive form non-alcoholic steatohepatitis (NASH) and the newly coined metabolic dysfunction-associated steatotic liver disease (MASLD). Recent advances highlight how dysregulated Ca2+ dynamics intersect with nutrient-sensing kinases, microRNAs and genetic variants to influence disease onset and progression. Therapeutic strategies that restore Ca2+ homeostasis—by modulating SERCA, stabilising MAM integrity or activating AMPK-driven pathways—are emerging as promising avenues to reverse steatosis, reduce ER stress and ultimately improve liver function.

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Calcium Signaling in Liver Metabolism Disorders publication trend

The graph below shows the total number of articles in calcium signaling in liver metabolism disorders across all publications each year (not limited to Nature Index journals).

Technical terms

Sarco/endoplasmic reticulum Ca2+-ATPase (SERCA): A pump that translocates Ca2+ from the cytosol into the ER lumen to maintain intracellular Ca2+ stores and prevent prolonged cytosolic elevation.

Mitochondria-associated membranes (MAMs): Specialized contact sites between the ER and mitochondria facilitating lipid and Ca2+ exchange essential for energy production and organelle communication.

Endoplasmic reticulum stress (ER stress): A condition arising from accumulated misfolded proteins in the ER, triggering adaptive responses that can become pathological if sustained.

Store-operated calcium entry (SOCE): A mechanism by which depletion of ER Ca2+ stores activates plasma-membrane channels to allow extracellular Ca2+ influx and restore ER function.

AMP-activated protein kinase (AMPK): A cellular energy sensor kinase that, when activated, promotes catabolic pathways and can enhance SERCA expression to mitigate ER stress.

MicroRNA (miRNA): Small non-coding RNA molecules that post-transcriptionally regulate gene expression, including factors involved in Ca2+ signalling and metabolic pathways.

References

1. Metformin’s effect on metabolic dysfunction-associated steatotic liver disease through the miR-200a-5p and AMPK/SERCA2b pathway. Frontiers in Pharmacology (2024).
2. Genetic polymorphisms of Ca2+ transport proteins and molecular chaperones in mitochondria-associated endoplasmic reticulum membrane and non-alcoholic fatty liver disease. Frontiers in Endocrinology (2023).
3. Endoplasmic Reticulum and Mitochondria Contacts Correlate with the Presence and Severity of NASH in Humans. International Journal of Molecular Sciences (2022).