Shark liver oil supplementation enriches endogenous plasmalogens and reduces markers of dyslipidemia and inflammation.

Plasmalogens are membrane glycerophospholipids with diverse biological functions. Reduced plasmalogen levels have been observed in metabolic diseases; hence, increasing their levels might be beneficial in ameliorating these conditions. Shark liver oil (SLO) is a rich source of alkylglycerols that can be metabolized into plasmalogens. This study was designed to evaluate the impact of SLO supplementation on endogenous plasmalogen levels in individuals with features of metabolic disease. In this randomized, double-blind, placebo-controlled cross-over study, the participants (10 overweight or obese males) received 4-g Alkyrol® (purified SLO) or placebo (methylcellulose) per day for 3 weeks followed by a 3-week washout phase and were then crossed over to 3 weeks of the alternate placebo/Alkyrol® treatment. SLO supplementation led to significant changes in plasma and circulatory white blood cell lipidomes, notably increased levels of plasmalogens and other ether lipids. In addition, SLO supplementation significantly decreased the plasma levels of total free cholesterol, triglycerides, and C-reactive protein. These findings suggest that SLO supplementation can enrich plasma and cellular plasmalogens and this enrichment may provide protection against obesity-related dyslipidemia and inflammation.

Oral Supplementation of an Alkylglycerol Mix Comprising Different Alkyl Chains Effectively Modulates Multiple Endogenous Plasmalogen Species in Mice.

Plasmalogens or alkenylphospholipids are a sub-class of glycerophospholipids with numerous biological functions and are thought to have protective effects against metabolic disease. Dietary supplementation with alkylglycerols (AKGs) has been shown to increase endogenous plasmalogen levels, however effective modulation of different molecular plasmalogen species has not yet been demonstrated. In this study, the effects of an orally-administered AKG mix (a mixture of chimyl, batyl and selachyl alcohol at a 1:1:1 ratio) on plasma and tissue lipids, including plasmalogens, was evaluated. Mice on a Western-type diet were treated with either an AKG mix or vehicle (lecithin) for 1, 2, 4, 8 and 12 weeks. Treatment with the AKG mix significantly increased the total plasmalogen content of plasma, liver and adipose tissue as a result of elevations in multiple plasmalogen species with different alkenyl chains. Alkylphospholipids, the endogenous precursors of plasmalogens, showed a rapid and significant increase in plasma, adipose tissue, liver and skeletal muscle. A significant accumulation of alkyl-diacylglycerol and lyso-ether phospholipids was also observed in plasma and tissues. Additionally, the dynamics of plasmalogen-level changes following AKG mix supplementation differed between tissues. These findings indicate that oral supplementation with an AKG mix is capable of upregulating and maintaining stable expression of multiple molecular plasmalogen species in circulation and tissues.

Plasmalogens: A potential therapeutic target for neurodegenerative and cardiometabolic disease.

Plasmalogens are a class of membrane glycerophospholipids with unique properties. They contain a vinyl-ether linked alkyl chain at the sn-1 position of the glycerol backbone and, typically, a polyunsaturated fatty acyl chain at the sn-2 position. Plasmalogens are critical for human health and have established roles in neuronal development, the immune response and as endogenous antioxidants. However, the mechanistic bases of these and other biological functions of plasmalogens are not well defined. Lipidomic studies have characterised reduced levels of plasmalogens in a number of disease states, including neurodegenerative and cardiometabolic disease, highlighting the potential of plasmalogen modulation as a therapeutic strategy. A number of approaches have been proposed to upregulate plasmalogen levels in different clinical settings; these include dietary intervention with inositol or the naturally occurring metabolic precursors known as alkylglycerols. Plasmalogen modulation has been utilised in both preclinical and clinical studies to prevent onset and/or attenuate progression of neurodegenerative diseases, atherosclerosis, insulin resistance and hepatosteatosis. These studies are providing new insight into the mechanistic role of plasmalogens in disease and their therapeutic potential. In this review, we will examine the strategies for plasmalogen modulation and recent progress toward therapeutic applications with a focus on neurodegenerative and cardiometabolic disease.

HSP72 protects against obesity-induced insulin resistance.

Patients with type 2 diabetes have reduced gene expression of heat shock protein (HSP) 72, which correlates with reduced insulin sensitivity. Heat therapy, which activates HSP72, improves clinical parameters in these patients. Activation of several inflammatory signaling proteins such as c-jun amino terminal kinase (JNK), inhibitor of kappaB kinase, and tumor necrosis factor-alpha, can induce insulin resistance, but HSP 72 can block the induction of these molecules in vitro. Accordingly, we examined whether activation of HSP72 can protect against the development of insulin resistance. First, we show that obese, insulin resistant humans have reduced HSP72 protein expression and increased JNK phosphorylation in skeletal muscle. We next used heat shock therapy, transgenic overexpression, and pharmacologic means to overexpress HSP72 either specifically in skeletal muscle or globally in mice. Herein, we show that regardless of the means used to achieve an elevation in HSP72 protein, protection against diet- or obesity-induced hyperglycemia, hyperinsulinemia, glucose intolerance, and insulin resistance was observed. This protection was tightly associated with the prevention of JNK phosphorylation. These findings identify an essential role for HSP72 in blocking inflammation and preventing insulin resistance in the context of genetic obesity or high-fat feeding.

Effects of carbohydrate supplementation on performance and carbohydrate oxidation after intensified cycling training.

To study the effects of carbohydrate (CHO) supplementation on performance changes and symptoms of overreaching, six male endurance cyclists completed 1 wk of normal (N), 8 days of intensified (ITP), and 2 wk of recovery training (R) on two occasions in a randomized crossover design. Subjects completed one trial with a 6% CHO solution provided before and during training and a 20% solution in the 1 h postexercise (H-CHO trial). On the other occasion, subjects consumed a 2% CHO solution at the same time points (L-CHO). A significant decline in time to fatigue at approximately 63% maximal power output (H-CHO: 17 +/- 3%; L-CHO: 26 +/- 7%) and a significant increase in mood disturbance occurred in both trials after ITP. The decline in performance was significantly greater in the L-CHO trial. After ITP, a significant decrease in estimated muscle glycogen oxidation (H-CHO: N 49.3 +/- 2.9 kcal/30 min, ITP 32.6 +/- 3.4 kcal/30 min; L-CHO: N 49.1 +/- 30 kcal/30 min, ITP 39.0 +/- 5.6 kcal/30 min) and increase in fat oxidation (H-CHO: N 16.3 +/- 2.4 kcal/30 min, ITP 27.8 +/- 2.3 kcal/30 min; L-CHO: N 16.9 +/- 2.6 kcal/30 min, ITP: 25.4 +/- 3.5 kcal/30 min) occurred alongside significant increases in glycerol and free fatty acids and decreases in free triglycerides in both trials. An interaction effect was observed for submaximal plasma concentrations of cortisol and epinephrine, with significantly greater reductions in these stress hormones in L-CHO compared with H-CHO after ITP. These findings suggest that CHO supplementation can reduce the symptoms of overreaching but cannot prevent its development. Decreased endocrine responsiveness to exercise may be implicated in the decreased performance and increased mood disturbance characteristic of overreaching.