J Lipid Res. 2023 Jul 18:100413. doi: 10.1016/j.jlr.2023.100413. Online ahead of print.

ABSTRACT

Alcoholic-related liver disease (ALD) is one of the leading causes of chronic liver disease and morbidity. Unfortunately, the pathogenesis of ALD is still incompletely understood. Steroidogenic acute regulatory protein (StARD1) has emerged as a key player in other etiologies of chronic liver disease, and alcohol-induced liver injury exhibits zonal distribution. Here, we report that StARD1 is predominantly expressed in perivenous (PV) zone of liver sections from mice fed chronic and acute-on-chronic ALD models compared to periportal (PP) area. The zonal distribution of StARD1 is observed as early as 10 days of alcohol feeding in isolated PV compared to PP hepatocytes. Ethanol and chemical hypoxia induced the expression of StARD1 in isolated primary mouse hepatocytes. The zonal-dependent expression of StARD1 resulted in the accumulation of cholesterol in mitochondria and increased lipid peroxidation in PV hepatocytes from mice fed alcohol compared to PP hepatocytes, effects that were abrogated in PV hepatocytes upon hepatocyte-specific Stard1 knockout mice. We observed unchanged zonal distribution of bile acids in alcohol-fed mice. Transmission electron microscopy (TEM) indicated basal differential glycogen and lipid droplets content (LD) between PP and PV areas, and alcohol feeding decreased glycogen content in both areas, while increased LD preferentially in PV zone. Moreover, TEM revealed that mitochondria from PV zone exhibited reduced length with respect to PP area, and alcohol feeding increased mitochondrial number, particularly, in PV zone. Extracellular flux analysis indicated lower maximal respiration and spared respiratory capacity in control PV hepatocytes that were reversed upon alcohol feeding. These findings reveal a differential morphology and functional activity of mitochondria between PP and PV hepatocytes following alcohol feeding and that StARD1 may play a key role in the zonal-dependent liver injury characteristic of ALD.

PMID:37473919 | DOI:10.1016/j.jlr.2023.100413