Why Low-Carb Diets Can Trigger Cholesterol Spikes Based on Your DNA

That is the central hypothesis emerging from a secondary analysis of the DIETFITS trial, presented at NUTRITION 2026, the American Society for Nutrition's annual meeting.

Alexa Barad, PhD, RDN, a postdoctoral scholar at Stanford University School of Medicine, reported that participants assigned to a healthy low-carb diet who carried a high polygenic predisposition to elevated LDL cholesterol experienced sharp increases in cholesterol when saturated fat intake rose. The same interaction was absent in the low-fat arm.

The cohort and the signal

The analysis used genetic data from 431 participants in DIETFITS — a randomized controlled trial of more than 600 adults assigned to either a healthy low-carb or healthy low-fat diet for 12 months. The original trial found no significant advantage for either diet on weight loss.

For this secondary analysis, researchers aggregated thousands of genomic variants into a polygenic score estimating each participant's inherited tendency toward higher or lower LDL cholesterol, then correlated that score against changes in LDL from baseline to six months.

Three outcomes warrant attention:

• The LDL-raising effect of saturated fat was concentrated in the low-carb arm; the same association was not observed in the low-fat arm.
• Among low-carb participants, those in the highest polygenic risk tertile showed the largest LDL increases when saturated fat consumption rose.
• The interaction suggests that saturated fat sensitivity — not carbohydrate restriction per se — is the primary biochemical driver of the adverse lipid response.

Why saturated fat, specifically

Dietary saturated fatty acids — predominantly myristic (C14:0), palmitic (C16:0), and lauric (C12:0) — suppress hepatic LDL receptor expression, reducing fractional clearance of circulating LDL particles. Within a low-carbohydrate framework, where saturated fat often displaces carbohydrate calories, the substrate load on this clearance pathway rises. Inherited variation across loci involved in lipid metabolism — including LDLR, APOB, and PCSK9 — appears to modulate the magnitude of that response.

"Our findings suggest that some individuals may be more sensitive to the LDL cholesterol-raising effects of saturated fat, particularly in the context of a low-carbohydrate diet, because of their genetic background," Barad said.

"There is real heterogeneity in how people respond to diet," she added. "Dietary conversations can sometimes become overly simplified. One person may say, 'Low-carb diets always raise LDL cholesterol,' while another says, 'My LDL cholesterol did not change at all.' Our findings suggest that both experiences can be true."

What to verify before changing the diet

The findings are associative, not prescriptive. They do, however, suggest a reasonable sequence of checks for anyone following or considering a low-carbohydrate pattern:

• Establish a baseline lipid panel — total cholesterol, LDL-C, HDL-C, triglycerides — and re-test at three to six months.
• Quantify saturated fat as a percentage of total calories; the effect signal tracked with saturated fat intake, not carbohydrate restriction alone.
• If LDL-C rises meaningfully from baseline, discuss dietary composition adjustment — not necessarily carbohydrate restoration — with a clinician.
• Recognize that polygenic LDL risk scores are not yet standard clinical tools; predictive validity across commercial platforms varies.

The hypothesis advanced by the Stanford group is testable and falsifiable. Until a prospective trial stratifies participants by polygenic score before randomization, the data argue against treating "low-carb" as a monolithic intervention and support targeted monitoring of the macronutrient — saturated fat — that appears to interact with inherited lipid metabolism.