The liver coordinates macronutrient metabolism and is vulnerable to perturbation by both chronic alcohol exposure and systemic cancer. Cancer-induced cachexia involves systemic metabolic reprogramming that affects peripheral tissues including the liver. This study examined whether prior alcohol use and alcohol cessation modify hepatic gene expression for lipid metabolism and protein content of mitochondrial/mitophagy pathways in a distal-site cancer cachexia model.
Male CD2F1 mice were randomized into six groups to separate effects of cancer, ongoing alcohol, and prior alcohol followed by cessation. The groups were: Control no cancer, Control-Cancer, prior alcohol (PE), PE-cancer, EtOH (current alcohol), and EtOH-cancer. Alcohol exposure consisted of a liquid diet where ethanol contributed 20% of kcal and lasted 6 weeks; mice in PE groups were weaned off alcohol after this period prior to tumor implantation.
Cachexia was induced using C26 colon carcinoma cells implanted at a distal site. Two weeks following tumor implantation, livers were collected for downstream molecular analyses. The protocol included extraction of RNA, conversion to cDNA, RT-PCR for gene expression, and Western blotting to quantify protein content.
Measured endpoints reported in the source included hepatic mRNA levels for genes involved in lipid uptake, cholesterol synthesis, de novo lipogenesis, and lipolysis, as well as protein content of mitochondrial respiratory chain complexes and mitophagy-related proteins. Specific assays noted were RT-PCR for transcripts and Western blot for proteins such as the mitochondrial complex V subunit vATP5A and mitophagy regulators DRP-1 and BNIP3.
The presence of cancer produced classic cachexia-related phenotypes: lower total body weight and reduced epididymal adipose tissue mass. Cancer-bearing mice exhibited increased absolute liver weight and a greater percent body weight loss when compared with non-cancer controls. At the molecular level, distal-site cancer increased expression of hepatic genes related to lipid uptake and cholesterol synthesis, while suppressing genes involved in de novo lipogenesis and lipolysis in the liver.
Alcohol exposure alone also increased liver weight and reduced fat mass compared with controls. Notably, mice that had been exposed to alcohol and then underwent cessation (PE) showed attenuation of cancer-associated body weight loss relative to mice that continued alcohol exposure during cancer, indicating that alcohol cessation partially mitigated whole-body weight loss in the cachexia model.
Cancer shifted hepatic lipid-related gene expression toward increased uptake and cholesterol synthesis, while downregulating pathways for new lipid synthesis and lipid breakdown. In non-cancer mice, the cessation of alcohol decreased expression of genes involved in cholesterol synthesis. The source abstract does not provide detailed lists of specific genes, fold changes, or p values; those quantitative details were not reported in the provided text.
Distal-site cancer reduced hepatic mitochondrial respiratory chain protein content and decreased levels of mitophagy-related proteins DRP-1 and BNIP3. Alcohol exposure by itself also lowered DRP-1 and BNIP3 content in the liver. In mice without cancer, alcohol cessation increased levels of the complex V protein vATP5A of the mitochondrial respiratory chain. Overall, while cessation altered some mitochondrial protein markers in non-cancer animals, it produced fewer changes in mitochondrial proteins in the context of cancer.
In this murine C26 cachexia model, prior alcohol exposure and ongoing alcohol both affected liver mass and fat stores. Importantly, stopping alcohol consumption before tumor challenge attenuated cancer-associated body weight loss but had limited impact on cancer-driven reductions in hepatic mitochondrial proteins and on the pattern of genes regulating hepatic lipid balance. The findings suggest alcohol cessation yields some protective effect against whole-body weight loss in cancer cachexia but does not fully reverse cancer-induced hepatic mitochondrial or lipid gene alterations.
Note: The abstract provided summarizes experimental design and directional results; detailed quantitative values, sample sizes, and statistical significance metrics were not included in the source text and are therefore not reported here.