Compensatory Enzyme Expression In Response To Chronic Ethanol Intake And Partial Hepatectomy Disrupts Zone‐Specific Organization Of Lobular Metabolism In The Rat Liver

Abstract

Regulation of liver metabolism is heterogeneous across lobular zones. In response to the acute metabolic challenge of partial hepatectomy (PHx), hepatocytes enact a global transcriptional program both to compensate for and replace lost tissue mass. Chronic ethanol intake has also been shown to rewire transcriptional programs in hepatocytes, with suppressive effects on hepatocyte proliferation and blunted regeneration post PHx. However, it is not clear how zone‐specific metabolism transiently adjusts to ensure PHx‐induced regeneration, or how zone‐specific metabolism is adapted due to chronic insult by ethanol intake.Male Sprague‐Dawley rats were fed a Lieber‐DeCarli liquid diet containing ethanol or carbohydrate for 5–6 weeks prior to 70% PHx in which left lateral and medial lobes were surgically removed. Liver tissue samples were collected at the time of surgery and after 24 hours of recovery. Laser‐capture microdissection was used to collect regions of tissue from eight distinct lobular zones between portal triads and central veins, and high throughput qPCR was used for transcriptional analysis.We show here that regrowth after PHx involves multiple patterns of compensatory gene expression of enzymes from most major metabolic pathways. Genes whose expression is normally restricted to a particular zone responded to PHx in a wide range of patterns, e.g., by increasing expression with no change of zone (e.g., Arg1), expanding expression to nearby zones (e.g., Glul), or transient uniform expression across the whole lobule (e.g., Ldha). We tested whether chronic ethanol intake dysregulates zonation patterns of gene expression by exaggerating, dampening, redistributing, or eliminating preexisting lobular heterogeneity. After PHx, chronic ethanol intake dysregulated zonation of expression patterns in a variety of ways, including a reversal of healthy adaptations (e.g., Pck1). Other ethanol‐induced patterns of expression seen were suppression of PHx‐induced expression (e.g., Ldha) and redistribution of expression (e.g., Arg1).The dysregulation of zonated metabolic gene expression patterns in chronic‐ethanol‐fed rats suggests that zone‐specific compensatory mechanisms may contribute to the ethanol‐impaired liver regeneration post‐PHx. Overall, this work shows the transient changes in zone‐specific transcriptional regulation in response to PHx, and identifies genes whose zone‐specific expression is affected early in ethanol‐induced disease progression. These heterogeneous changes within the hepatic lobule could be a marker of ethanol‐induced adaptation preceding more severe impairment.Support or Funding InformationSupported by NIH NIAAA R01 AA018873, T32 AA007463, and NIBIB U01 EB023224.