Diroleuton

Intracellular lipid binding proteins (iLBPs) play crucial roles in lipid transport and cellular metabolism across the animal kingdom. Recently, a fat‐to‐neuron axis was described in Caenorhabditis elegans, in which lysosomal activity in the fat liberates polyunsaturated fatty acids (PUFAs) that signal to neurons and extend lifespan with durable fecundity. In this study, we investigate the structure and binding mechanisms of a lifespan‐extending lipid chaperone, lipid binding protein‐3 (LBP‐3), which shuttles dihomo‐γ‐linolenic (DGLA) acid from intestinal fat to neurons. We present the first high‐resolution crystal structure of LBP‐3, which reveals a classic iLBP fold with an unexpected and unique homodimeric arrangement via interstrand interactions that is incompatible with ligand binding. We identify key ionic interactions that mediate DGLA binding within the lipid binding pocket. Molecular dynamics simulations further elucidate LBP‐3's preferential binding to DGLA due to its rotational freedom and access to favorable binding conformations compared to other 20‐carbon PUFAs. We also propose that LBP‐3 dimerization may be a unique regulatory mechanism for lipid chaperones.

n-6 PUFA, especially linoleic acid (LA) but also arachidonic acid (AA), have been inversely associated with CHD. However, mechanisms underlying these associations are not fully known. We investigated the associations of the serum concentrations of total n-6 PUFA, LA, AA, γ-linolenic acid (GLA) and dihomo-γ-linolenic acid (DGLA), with the odds of myocardial ischaemia during exercise, a predictor of future cardiac events. A total of 1871 men without a history of CHD from the Kuopio Ischaemic Heart Disease Risk Factor Study (KIHD) aged 42–60 years were included. All participants performed a maximal symptom-limited exercise stress test, using an electrically braked bicycle ergometer. Multivariable-adjusted logistic regression was used to assess the OR for exercise-induced myocardial ischaemia in quartiles of the serum n-6 PUFA concentrations. After multivariable adjustment, men in the highest v. the lowest serum AA concentration had 50 % lower odds for exercise-induced myocardial ischaemia (OR 0·50, 95 % CI 0·34, 0·76; P-trend across quartiles < 0·001). For the other PUFA, the OR (95 % CI) were 1·00 (0·69, 1·46; P-trend = 0·89) for LA, 1·07 (0·75, 1·53; P-trend = 0·40) for GLA and 0·74 (0·51, 1·07; P-trend = 0·16) for DGLA. Among the n-6 PUFA, higher serum concentration of AA was associated with lower odds for myocardial ischaemia during an exercise test in middle-aged and older men. This may provide one mechanism for the previously observed possible cardioprotective properties of AA. Our findings also suggest that n-6 PUFA should not be considered as one homogenous group.