Triglyceride accumulation protects against fatty acid-induced lipotoxicity

TLDR

Excess lipid accumulation in non‑adipose tissues is linked to insulin resistance, β‑cell apoptosis, and heart failure. The study demonstrates that the toxicity of two common dietary long‑chain fatty acids depends on their metabolic routing in cultured cells. Oleic acid promotes triglyceride accumulation and protects cells from palmitate‑induced apoptosis, whereas palmitic acid is poorly incorporated into triglycerides and triggers apoptosis; when triglyceride synthesis is impaired, oleate itself becomes lipotoxic.

Abstract

Excess lipid accumulation in non-adipose tissues is associated with insulin resistance, pancreatic β-cell apoptosis and heart failure. Here, we demonstrate in cultured cells that the relative toxicity of two common dietary long chain fatty acids is related to channeling of these lipids to distinct cellular metabolic fates. Oleic acid supplementation leads to triglyceride accumulation and is well tolerated, whereas excess palmitic acid is poorly incorporated into triglyceride and causes apoptosis. Unsaturated fatty acids rescue palmitate-induced apoptosis by channeling palmitate into triglyceride pools and away from pathways leading to apoptosis. Moreover, in the setting of impaired triglyceride synthesis, oleate induces lipotoxicity. Our findings support a model of cellular lipid metabolism in which unsaturated fatty acids serve a protective function against lipotoxicity though promotion of triglyceride accumulation.