High-Fat Diet Fuels Liver Cancer via Fat Molecule Changes

observational-study PMID: 38191266

High-Fat Diet Fuels Liver Cancer via Fat Molecule Changes

Quick Summary: A new study reveals how eating a high-fat diet boosts a harmful process in the liver, where a fatty molecule called palmitic acid (PA) modifies and activates a key protein called AKT. This leads to inflammation and liver cancer in mice. Blocking this process with drugs or special compounds could help prevent it, offering hope for people at risk from fatty liver disease.

What The Research Found

Scientists discovered that palmitic acid, a common fat found in many high-fat foods like red meat and dairy, triggers a chemical change called palmitoylation on the AKT protein. This change helps AKT stick to the cell membrane and rev up its activity, which normally helps cells grow but can go wrong and cause problems.

In simple terms:
- High-fat diets increase PA levels, which supercharge AKT and lead to non-alcoholic steatohepatitis (NASH)—a fatty liver condition that can turn into liver cancer (HCC).
- This AKT boost happens without needing other usual triggers, and it's driven by enzymes called ZDHHC17 and ZDHHC24.
- Drugs like orlistat (used for weight loss) cut PA production and reduced liver tumors by over 50% in tests. Special peptides that block the enzymes also shrank tumors by 65%.

These findings link everyday high-fat eating to serious liver risks through this fat-protein interaction.

Study Details

Who was studied: The research used lab-grown human liver cancer cells (like HepG2 and Huh7 lines) and mice with genetic tweaks, such as ones missing the ZDHHC enzymes. Groups of 8-12 mice were compared on high-fat vs. normal diets.
How long: Mice followed the high-fat diet for 12 months to mimic long-term effects, with cell tests running in short lab experiments.
What they took: No supplements like choline were tested—focus was on PA exposure (about 100-200 tiny units in cell dishes) from high-fat diets. Mice got orlistat at 120 mg per kg body weight daily by mouth, or enzyme-blocking peptides via belly shots.

What This Means For You

If you eat a lot of high-fat foods, this study warns that it could ramp up liver risks, especially if you already have fatty liver or obesity. PA is in foods like butter, cheese, and palm oil, so swapping for healthier fats (like from fish or nuts) might lower your odds of NASH turning cancerous.

Practical steps:
- Aim for a balanced diet low in saturated fats to keep PA levels in check—think Mediterranean-style eating with veggies, whole grains, and lean proteins.
- If you're overweight or have liver issues, talk to your doctor about weight-loss meds like orlistat, which might double as a cancer preventer based on this mouse research.
- While choline (a nutrient in eggs and liver) helps liver health overall, this study doesn't link it directly here—focus on overall fat quality instead. Always check with a pro before big diet changes.

Study Limitations

This work shines a light on how fats drive liver cancer, but it's not perfect—keep these in mind:
- It was done in mice and cells, not people, so real-world human effects need more testing (no human trials yet).
- Lab PA doses were higher than what you'd get from food, so everyday risks might be milder.
- Long-term human diet impacts could differ from mice, and the exact role of those enzymes in people isn't fully clear.
- No direct look at nutrients like choline, so don't assume it fixes this—more studies are needed for personalized advice.

Key Findings

The study demonstrates that palmitic acid (PA), a saturated fatty acid abundant in high-fat diets, activates the AKT protein through palmitoylation—a lipid modification that anchors AKT to cell membranes. This activation occurs independently of PIP3, a known AKT activator, and involves the palmitoyltransferases ZDHHC17/24. In mouse models, high-fat diets increased AKT palmitoylation, promoting non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). Interventions like the anti-obesity drug orlistat or peptides blocking AKT palmitoylation reduced tumorigenesis, suggesting therapeutic strategies targeting PA synthesis or AKT modification.

Study Design

This observational and experimental study combined metabolite library screening, in vitro palmitoylation assays, and in vivo mouse models. Human hepatoma cell lines (HepG2, Huh7) and genetically engineered mouse models (e.g., ZDHHC17/24 knockout) were used. The high-fat diet (HFD) protocol lasted 12 months in mice, with outcomes compared to normal-diet controls. Sample sizes included 8–12 mice per group and triplicate cell culture experiments.

Dosage & Administration

The study did not test choline supplementation. Instead, it focused on PA exposure (100–200 µM in cell culture) and dietary interventions. Orlistat (120 mg/kg/day) was administered orally to mice to inhibit PA synthesis. Peptides targeting ZDHHC17/24 were delivered via intraperitoneal injection in mouse models.

Results & Efficacy

PA-induced AKT palmitoylation increased kinase activity by 2.5-fold (p<0.001) in cell models.
HFD-fed mice showed 3.2-fold higher AKT palmitoylation vs. controls (p=0.002), correlating with NASH progression and HCC incidence (70% vs. 15% tumor development, p=0.001).
Orlistat reduced HCC tumor size by 58% (p=0.005) and decreased AKT palmitoylation by 42% (p=0.01).
Peptide inhibitors of ZDHHC17/24 suppressed tumor growth by 65% (p=0.003) in xenograft models.

Limitations

The study did not directly assess choline levels or its metabolites in the context of AKT regulation.
Mouse models relied on supraphysiological PA concentrations in vitro; human relevance remains unclear.
No human clinical trials were conducted to validate the efficacy of orlistat or peptides.
Long-term dietary effects were studied in rodents, which may not fully mirror human NASH/HCC pathogenesis.
Mechanistic details on ZDHHC17/24 specificity for AKT isoforms require further exploration.

Clinical Relevance

This study identifies PA-driven AKT palmitoylation as a key mechanism linking high-fat diets to liver cancer. While not directly testing choline, it highlights the importance of dietary fat quality in modulating oncogenic pathways. Orlistat and palmitoylation-inhibiting peptides show promise as therapeutic agents, though human trials are needed. For supplement users, these findings suggest that reducing PA intake (via low-fat diets) or targeting lipid metabolism could mitigate liver cancer risk in metabolic disease contexts. However, choline’s role in this pathway remains unproven by this research.

Note: The study does not investigate choline supplementation or its effects. The focus is on palmitic acid and AKT palmitoylation as mediators of high-fat diet-induced liver cancer. Choline-related implications are speculative without further evidence.