Alcohol’s impact on markers of hepatic metabolism in male mice during distal site cancer

Alcohol increases the risk of several types of cancer. Alcohol is metabolized primarily in the liver and causes significant metabolic dysfunction leading to the accumulation of lipids and eventually development of alcohol associated liver disease if heavy drinking is continued. The objective of the current work was to determine whether alcohol intake before and during distal site cancer was linked to changes in liver metabolic pathways presumably altering whole body metabolism. It was hypothesized that alcohol intake would lead to changes in proteins and genes central to macronutrient metabolism as well as mitochondrial function in the liver. METHODS: Male CD2F1 mice (n=42) randomized across 4 groups: Control no cancer; Control Cancer; alcohol no cancer; or alcohol cancer. Mice were fed either control or alcohol-containing (ETOH) (20% kcals from ethanol) liquid diet. C26 colon carcinoma cells (1x10 6 cells/250mL) were placed in the flank after 6 weeks of alcohol intake. Two weeks later, liver tissue was collected and processed for RNA, cDNA, RT-PCR and Western blotting. Two-way ANOVA analysis (factors: Cancer or EtOH) was performed with significance set to p<0.05. RESULTS: At end point, there was a significant main effect of both cancer and ETOH to reduce body weight and increase liver weight relative to body weight. Within the liver, protein phosphorylation of key components (rpS6, AKT, AMPK, ULK) of the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway were largely unchanged by alcohol and cancer except for mTOR Ser2481 that was increased in cancer and ETOH groups. Genes implicated in fat and carbohydrate metabolism that were decreased with cancer included Pparα, Srebp1, Hadh, Pck1, Scd1 and Fasn. Alternatively, a main effect to increase cholesterol metabolism genes (Dhcr24 and Hmgcs1) as well as fatty acid transporter Cd36 was also observed with cancer. A main effect of EtOH to increase the following was observed: Pparα, ACC Ser79 and Pgc1α. Cancer and ETOH influenced several mitochondrial proteins including a main effect of cancer and ETOH to decrease NDUFB8, Cytochrome C, DRP1, and BNIP3, while there was a main effect of cancer to decrease SDBH, MTCO1, and COX IV and for ETOH to increase vATP5A. CONCLUSION: Distal site cancer leads to significant metabolic disruption in the liver that is only minorly exacerbated by previous and continued alcohol intake. While a significant limitation of this work is the lack of assessment of the degree of alcohol associated liver disease prior to cancer initiation, the effects of prior and continued alcohol intake on liver metabolism during cancer appear to be selective and secondary to those imposed by the cancer itself. FUNDING: Florida Department of Health Grant # 9BC03 to JLS. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.