PhD Candidate Laval University Québec, Quebec, Canada
Background: Metabolic dysfunction–associated steatotic liver disease (MASLD) affects up to one-third of adults in North America and is strongly associated with insulin resistance (IR). With no approved pharmacological treatment, dietary interventions remain the cornerstone of management. However, evidence supporting specific macronutrient modifications remains limited. This study evaluated the effects of replacing dietary carbohydrates with unsaturated fatty acids on hepatic gene expression and clinical metabolic markers in individuals with IR.
METHODS AND RESULTS: In a randomized, double-blind, crossover trial, eight subjects with IR completed two 3-day isocaloric diets under fully controlled feeding conditions. The high-unsaturated fat (HF) diet provided 40%E carbohydrate, 45%E fat (20.3%E monounsaturated, 12.1%E polyunsaturated, 10%E saturated), and 15%E protein. The high-carbohydrate (CHO) control diet provided 65%E carbohydrate, 20%E fat (8.3%E monounsaturated, 4.3%E polyunsaturated, 5.8%E saturated), and 15%E protein. Liver biopsies were obtained after each dietary intervention and analyzed by RNA sequencing; fasting serum samples were collected for biochemical analysis. Consumption of the HF diet reduced fasting serum triglycerides (TGs) by 27.4% (P = 0.018), the total cholesterol (TC)/HDL-C ratio by 6.4% (P = 0.036), and insulin levels by 13.2% (P = 0.039) compared with the CHO diet. LDL-C, HDL-C, non-HDL-C, apoB, and glucose levels did not differ significantly between the diets. Transcriptomic analysis identified 20 differentially expressed genes with FDR < 0.05 between diets. Among them, CHI3L1 and SRCIN1, associated with inflammation and cytoskeleton regulation, were downregulated, whereas STARD4 and NDUFS8, involved in cholesterol transport and mitochondrial function, were upregulated after the HF diet. Gene set enrichment analysis (GSEA) revealed significantly downregulated pathways with FDR < 0.05 related to cellular stress responses, fibrosis, and cytoskeletal remodeling. At an exploratory threshold of FDR < 0.25, pathways related to fatty acid metabolism were upregulated (P = 0.001), while insulin secretion pathways were downregulated (P = 0.004), consistent with the observed reductions in serum TGs and insulin, respectively.
Conclusion: The short-term replacement of carbohydrates with unsaturated fatty acids induced transcriptome changes in the liver of individuals with IR, including the downregulation of genes involved in inflammation, cellular stress, and insulin secretion, and the upregulation of genes related to mitochondrial function, cholesterol transport, and fatty acid metabolism. These alterations could underlie the observed reductions in fasting serum TGs, TC/HDL-C ratio, and insulin levels, providing a plausible mechanistic basis for these metabolic improvements and supporting the use of unsaturated fat–enriched diets as a non-pharmacological strategy for the management of MASLD.
