Dose-response relationships of normal blood lipid levels in metabolic and endocrine diseases: mechanistic...

As major products of lipid metabolism, blood lipids not only participate in the maintenance of energy homeostasis and the formation of cellular structures, but are also closely involved in endocrine signaling regulation. Although hyperlipidemia is a well-recognized pathogenic factor, a systematic understanding of the potential effects of lipid fluctuations within the normal reference range on metabolic and endocrine homeostasis remains lacking. Current epidemiological evidence suggests that the relationship between blood lipid levels and health risk does not follow a single all-or-none threshold pattern. Even within the clinically defined normal range, variations in certain lipid components may still show dose-response relationships with disease risk, and this continuous effect appears to be complex and heterogeneous across different metabolic and endocrine disorders. This review aims to systematically summarize the available evidence regarding the associations between different lipid components within the normal range and the risk of major metabolic and endocrine diseases. Particular emphasis is placed on comparing the similarities and differences in dose-response relationships across disease spectra and on exploring their potential shared and disease-specific mechanisms, including lipotoxicity-mediated β-cell dysfunction, the early initiation of insulin resistance, and abnormalities in feedback regulation along endocrine axes. Overall, traditional static lipid reference values may not always adequately reflect an individual's true metabolic risk. Future research should move beyond the conventional concept of achieving lipid targets and shift toward more refined risk assessment based on dose-response relationships, with the aim of clarifying the risk gradients of different lipid components within the normal lipid range and the contexts in which they apply. Such efforts may provide a basis for the early identification of metabolic and endocrine diseases, lifestyle intervention, and individualized risk management.