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Citrus Fruit Extracts and Their Beneficial Effect on Metabolic Diseases



Citrus fruits such as oranges, mandarins, grapefruit, and acid citrus fruits, namely lemons, bergamots, and limes, are notably rich in flavonoid content and possess various bioactivities. Citrus fruit extract also influences the bioavailability of certain drugs by inhibiting cytochrome enzymes or the uptake process of drugs from the gut. Organic anion transporting polypeptides (OATPs)8 constitute an important family of sodium-independent transport proteins. Grapefruit juice and naringin were found to inhibit organic anion-transporting polypeptide 1A2 (OATP1A2)-mediated fexofenadine uptake and reduce the oral bioavailability of the drug .

Many of the bioactivities of citrus flavonoids appear to affect vascular endothelial cells. Bergamot (Citrus bergamia Risso), a less commercialized citrus fruit extract, showed potential antioxidant activity in human umbilical vein endothelial cells, and inhibited the activation of NF-κB . Water extracts of sweet orange peel prevented the tert-butyl hydroperoxide–induced cytotoxic effect of HepG2 cells at 50- to 500-μg/mL doses and inhibited TBARS generation, increased mitochondrial membrane potential and Bcl-2:Bax ratio, and decreased caspase-3 activation . Citrus fruit extracts were also observed to offer potential health benefit in diabetes and obesity. Mandarin fruit extracts (1% or 3% of the diet) improved the metabolic function of liver and restored the antioxidant enzymes in streptozotocin-induced diabetic rats . 

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Citrus unshiu extract (1% or 3% of the diet) administration for 10 wk in type 2 diabetic Goto-Kakizaki rats improved glucose tolerance . Insulin resistance in type 2 diabetes may also lead to hepatic steatosis accompanied by progressive inflammation of the liver. The antihyperglycemic effect of Citrus unshiu peel extract (2 g/100 g diet) supplementation in male C57BL/KsJ-db/db mice appeared to be partially mediated through the inhibition of hepatic gluconeogenic phosphoenolpyruvate carboxykinase mRNA expression and its activity and through the induction of insulin/glucagon secretion . Mice supplemented with Citrus unshiu peel extract also displayed a significant decrease in body weight gain and body fat mass. Citrus unshiu extract also ameliorated hepatic steatosis and hypertriglyceridemia via the inhibition of gene expression and increased activation of lipogenic enzymes and FA oxidation in the liver . These beneficial effects of Citrus unshiu might be related to increased concentrations of anti-inflammatory adiponectin and IL-10, and decreased concentrations of proinflammatory markers [IL-6, monocyte chemotactic protein 1 (MCP-1), IFN-γ, and TNF-α] in the plasma or liver . Similarly, Citrus sunki extract at a dose of 150 mg · kg−1 · d−1 reduced body weight gain, adipose tissue weight, serum total cholesterol, and TG and serum concentrations of aspartate transaminase (AST), alanine transaminase (ALT), and alkaline phosphatase (ALP) in high-fat-diet–fed mice and prevented liver steatosis . Hepatic protection and the lipid-lowering effect of dietary supplementation of Citrus sunki extracts are mediated via upregulation of phosphorylation levels of AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC), which are related to FA β-oxidation . Citrus fruit extracts also inhibited the advanced glycation end product (AGE)– and H2O2-induced oxidative stress in human adipocytes . In a randomized clinical study, fresh grapefruit extracts reduced body weight and improved insulin resistance in obese patients . FFA release was used as an indicator of human adipocyte lipolysis. Citrus fruit extract at a dose 1.4 g/d increased human adipocyte lipolysis, probably by inhibiting cAMP-phosphodiesterase (cAMP-PDE)  or by enhancing phosphorylation of cAMP-dependent protein kinase A (PKA) and hormone-sensitive lipase (HSL) in mature 3T3-L1 adipocytes . These overall beneficial effects are summarized in Fig. 1.

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