Metabolic dysfunction-associated steatotic liver disease (MASLD) has become the most common chronic liver disorder worldwide, but the molecular basis through which the liver interprets nutritional status to decide whether to burn or store fat has remained poorly understood. Emerging evidence reveals that dysregulated autophagy, particularly the selective degradation of lipid droplets (lipophagy), is crucial to maintaining hepatic lipid balance, yet how its activity is regulated under different metabolic conditions has long been an open question.

In a recent study published in Life Metabolism, the research team led by Professor Hao Ying at the Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, reports that microRNA-378 (miR-378) serves as a metabolic-state-dependent molecular switch that determines the direction of hepatic autophagy and lipid accumulation through bile acid-mediated signaling. Under short-term fasting, miR-378 promotes lipid clearance by suppressing its target gene MAFG while bile acid levels remain low, thereby enhancing autophagy and facilitating the degradation of lipid droplets. In contrast, during prolonged fasting or high-fat feeding, miR-378 increases bile acid synthesis, leading to a substantial rise in hepatic bile acid levels. This shift activates the FXR–ACOX1–acetyl-CoA axis, which strongly inhibits autophagy and ultimately results in fat accumulation (Figure 1). The researchers also observed a striking spatial pattern within the liver: autophagy suppression was most prominent in periportal regions receiving bile acid-rich blood, highlighting the importance of hepatic zonation in metabolic regulation.

Mechanistically, the study uncovers a previously unrecognized regulatory pathway linking nutritional state, bile acid metabolism, and autophagy. Bile acids were found to activate the nuclear receptor FXR, upregulating ACOX1 and elevating hepatic acetyl-CoA levels. This rise in acetyl-CoA activates mTORC1, a well-established inhibitor of autophagy, effectively overriding miR-378’s pro-autophagic effects. Importantly, pharmacological inhibition of FXR using ursodeoxycholic acid (UDCA) restored autophagic flux, reduced acetyl-CoA accumulation, and alleviated hepatic steatosis in mouse models. The clinical relevance of this mechanism was supported by data from a cohort of 608 human participants, where circulating bile acid levels showed an independent association with hepatic steatosis.

Together, these findings establish that miR-378 serves as a metabolic-state-dependent switch that determines whether the liver activates or suppresses autophagy. Bile acids direct this shift through the FXR–ACOX1–acetyl-CoA pathway, offering new insight into MASLD progression and potential therapeutic strategies. Therapeutic strategies may need to differ by disease stage: enhancing miR-378 activity or inhibiting MAFG when bile acids are low, and targeting FXR or ACOX1 when bile acids are elevated in advanced disease.
DOI: 10.1093/lifemeta/loaf038