Chronic Alcohol Consumption Alters Rhythms in Key Enzymes and Transcription Factors Involved in Lipid Metabolism: Potential Role of the Circadian Clock

Chronic alcohol consumption disrupts hepatic lipid metabolism causing fatty liver disease or steatosis. The molecular and cellular mechanisms responsible for alcohol‐induced fat accumulation in hepatocytes remain unclear. New studies indicate that many metabolic processes, including lipid metabolism, are influenced by the molecular circadian clock. At the core of this molecular oscillator are the two transcription factors BMAL1 and CLOCK that drive rhythmic expression of other clock and clock‐regulated metabolic genes. We previously reported that chronic alcohol consumption disrupts the function of the molecular circadian clock in the liver. However, the impact this has on downstream clock‐regulated pathways, like lipid metabolism, is unknown. The purpose of this study was to determine whether chronic alcohol disrupts clock‐controlled rhythmic expression of triglyceride metabolism genes and transcription factors that regulate lipid metabolism. For these studies, male hepatocyte‐specific BMAL1 knockout (HBK) mice and their wild‐type (WT) control littermates were kept under a 12:12 hour light‐dark cycle and pair‐fed control or alcohol‐containing diets for 5 weeks. Livers were collected at 4‐hour intervals for a 24 hour period and gene expression was measured by qPCR. In WT alcohol‐fed mice, we observed a dampening in the diurnal rhythms in several triglyceride metabolism genes. Alcohol significantly decreased the diurnal gene expression rhythm of patatin‐like phospholipase domain‐containing 3 ( Pnpla3 ), an enzyme that mediates triglyceride breakdown. This result suggests that the alcohol‐mediated decrease in Pnpla3 may contribute, in part, to triglyceride accumulation in liver. Rhythmic expression of Pnpla3 was also completely abolished in liver of both control and alcohol‐fed HBK mice, suggesting a role of the clock in Pnpla3 regulation. The diurnal rhythm in acetyl CoA carboxylase 2 ( Acc2 ) was also decreased in livers of WT alcohol‐fed mice with further dampening observed in livers of HBK alcohol‐fed mice. Interestingly, the diurnal rhythm of Acc2 was phase shifted in the HBK control‐fed compared to WT controls. In addition, diurnal rhythms in sterol regulatory element binding protein 1c ( Srebp1c ) and Acc1 , both of which are involved in fatty acid synthesis, were also dampened in livers of WT and HBK alcohol‐fed mice. Overall, our findings indicate that chronic alcohol consumption disrupts normal diurnal rhythms of lipid metabolism processes, suggesting that alterations in the balance of these tightly regulated oscillations likely contribute to the alcoholic steatosis. Support or Funding Information This work is supported by NIH grant R01 AA020199