• Liver distress emerged despite lower body weight — The study found that even though mice on the ketogenic diet gained less weight than those fed a high-fat, high-carb diet, their liver profiles revealed signs of distress. Plasma triglycerides and non-esterified fats (free fatty acids released from stored fat) were significantly elevated, pointing to hyperlipidemia, a state of excess circulating fat in the bloodstream.

Male mice also developed hepatic steatosis (fat accumulation in the liver), along with increased alanine aminotransferase (ALT) activity. ALT is an enzyme concentrated inside liver cells and plays a role in amino acid metabolism. When liver cells are damaged or die, ALT leaks into the bloodstream, raising measurable levels. Elevated ALT directly reflects hepatocellular injury and indicates that the liver is under metabolic or inflammatory stress.

• Broader metabolic stress accompanied liver injury — Mice on the ketogenic diet developed glucose intolerance, meaning their bodies were less able to keep blood sugar stable after eating, and impaired insulin secretion, showing that the pancreas was not releasing enough insulin to regulate glucose. Together, these findings indicate that liver stress was part of a whole-body imbalance.

In particular, the pancreatic β cells (the cells that make and release insulin) showed disruptions in protein trafficking within the endoplasmic reticulum and Golgi apparatus, which fold and package proteins for secretion. This dysfunction resembled what is seen in early diabetes, where the machinery for insulin release becomes compromised.

• Microscopic evidence confirmed cellular damage — Electron microscopy revealed lipotoxic injury in the liver cells. The Golgi apparatus appeared dilated and fragmented, and genes linked to protein stress responses were upregulated. This pattern shows that long-term exposure to high lipid levels not only drives fat buildup but also interferes with protein processing and communication within cells, further aggravating liver dysfunction.

• Animal findings suggest parallels to human liver responses — Although this work was conducted in mice, the core mechanisms involved in fat regulation, glucose control, and protein processing are highly conserved across species. The authors wrote that their findings “have relevant translational ramifications” and “caution against the systematic use of a KD as a health-promoting dietary intervention.” The table below summarizes the animal findings alongside their human relevance:

Liver Outcomes — Enzymes and Steatosis

• Metabolic deterioration extends beyond the liver — In his analysis of the Science Advances study, bioenergetic researcher Georgi Dinkov added that chronic ketogenic patterns not only damage the liver but also suppress overall energy metabolism by reducing lean muscle mass. This has far-reaching metabolic consequences, since muscle is the most metabolically active tissue in the body and a major driver of resting energy use. These keto side effects often develop silently, without obvious symptoms. If you notice rising liver enzymes or a dull ache under your right rib cage, it may signal that your liver is under stress from the metabolic load. That’s the time to reassess your macronutrient balance before the strain turns chronic.

[…]

• LDL levels spiked dramatically in keto followers — The study reviewed clinical records of 17 adults who presented with LDL cholesterol levels above 190 milligrams per deciliter (mg/dL) while adhering to a high-fat, very-low-carb diet. Before starting keto, their mean LDL level was about 129 mg/dL. After roughly 12 months of strict adherence, that value rose by an average of 245%.

• ApoB reflects the number of cholesterol-carrying particles — Each LDL particle contains one molecule of apolipoprotein B (apoB), a structural protein that anchors cholesterol and triglycerides within the particle. ApoB therefore reflects not just how much cholesterol is present, but how many LDL particles are circulating. The more particles you have, the greater the chance they’ll penetrate inflamed artery walls and promote atherosclerosis, or plaque buildup.

• Genetic predisposition amplified the effect — Ten of the 17 patients had family histories of early heart disease or inherited lipid disorders. Five underwent genetic testing, and two carried mutations in the LDL receptor (LDL-R) gene, which impairs the body’s ability to remove LDL from circulation.

This means LDL particles linger in the blood longer, compounding the cholesterol rise. The researchers suggested that both diet composition and genetic background contributed to the extreme lipid response.

• Lean individuals showed the greatest LDL surge — The largest LDL increases appeared in participants with lower body mass index (BMI). The authors proposed that when carbohydrate intake is severely restricted, leaner individuals rely more heavily on fat oxidation, burning fat for fuel.

This shift ramps up production of very-low-density lipoprotein (VLDL) particles, which transport triglycerides from the liver. As VLDL offloads its fat cargo, it converts into LDL and HDL, explaining why even metabolically healthy or athletic people may see dramatic LDL spikes during keto adaptation.

• Stopping keto reversed the effects — In the study, when patients stopped the ketogenic diet, their LDL levels dropped by an average of 220% within nine months. This rebound emphasizes why anyone with a family history of early heart disease, lipid metabolism variants, or an unexplained rise in LDL or apoB while on keto should do so under medical supervision with regular lipid monitoring.

• Electrolyte loss drives early palpitations — When carbohydrate intake drops sharply, insulin levels fall and glycogen (stored carbohydrate) is depleted. This shift prompts the kidneys to excrete water along with key minerals, such as sodium, potassium, and magnesium.

These are the body’s electrolytes, which regulate the electrical signals that control heartbeat and muscle contraction. As they drop, the heart’s rhythm can become irregular or faster than usual (tachycardia), especially if hydration is inadequate. Replenishing electrolytes typically stabilizes symptoms within days.

• Fat-based fuel changes cardiac metabolism — Because ketogenic diets push the heart to depend almost entirely on fat oxidation instead of glucose for fuel, this metabolic shift can have unintended effects on cardiac performance, including disturbances in the heart’s electrical rhythm.

Experimental studies in animals also indicate that long-term ketogenic feeding may promote adverse remodeling of the heart muscle — characterized by fibrosis and changes in tissue structure — that can interfere with normal electrical conduction and raise the likelihood of arrhythmias such as atrial fibrillation.⁸

• When to address symptoms — Occasional palpitations during keto adaptation often resolve with hydration and mineral-rich foods like leafy greens and bone broth. However, ongoing rapid or irregular heartbeats, chest tightness, or palpitations accompanied by dizziness or shortness of breath require prompt evaluation. These may reflect electrical or structural strain on the heart, especially in individuals with high cholesterol, high blood pressure, or pre-existing heart disease.

• Simple checks before medical evaluation — Ensure adequate hydration, avoid caffeine and stimulant intake, and reassess whether palpitations persist once electrolytes stabilize. Thyroid hormone dosing, anemia, and overtraining can also contribute. If the symptoms continue after addressing these factors, a medical evaluation is essential. A basic electrocardiogram (ECG) and blood panel can identify early electrical or metabolic disturbances before they progress.