**7. New mechanisms exploration**

In the past recent years, new mechanisms of probiotics on lipid metabolism were proposed. A research by Khedara et al showed lower nitric oxide level has been responsible for hyperlipidemia since endogenous nitric oxide can reduce fatty acid oxidation [104]. Some probiotics had ability to induce nitric oxide synthesis through activation of inducible nitric oxide synthase [105] [106]. Thus, modied NO availability by probiotics play an important role in lipid metabolism.

Moreover, Tanida et al demonstrated that *Lactobacillus paracasei* ST11 could increase adipose tissue lipolysis through enhancing the autonomic nerve activity [107]. In liver, probiotics also exhibited lipid-reducing effects [108]. Ma et al demostrated that VSL#3 probiotics could increase hepatic NKT cell numbers to attenuate high fat diet-induced steatosis [109]. Huang et al found that *L. acidophilus* 4356 could downregulate the Niemann-Pick C1-Like 1 (NPC1L1) level in the duodenum and jejunum of high-fat fed rats [110]. Another recent study by Aronsson et al revealed a new mechanism of *Lactobacillus paracasei* F19 to reduce fat storage by up-regulating levels of Angiopoietin-Like 4 Protein (ANGPTL4) in mice [84].

Omics technology provide a new insight into the mechanisms of lipid metabolism influenced by probiotics. Lee et al demostrated that gene ccpA (encodes catabolite control protein A) had function in cholesterol reduction in vivo by comparation of cholesterolreducing strain *L. acidophilus* A4 and the BA9 mutant strain with no lipid-lowering effect [111]. In addition, six main different expressed proteins involved in these two different strains *in vitro* were identified by proteomic analysis including transcription regulator, FMN-binding protein, major facilitator superfamily permease, glycogen phosphorylase, YknV protein, and fructose/tagatose bisphosphate aldolase.

Microarray analysis of probiotic *L. casei* Zhang effect on liver of high fat diet-fed rats revealed that *L. casei* Zhang administration promote the β-oxidation of fatty acid metabolism through up-regulating five genes expression (Acsl1, Hadh, Acaa2, Acads, and gcdH). Moreover, *L. casei* Zhang could strongly activate expression of glucocorticoid receptor (NR3C1 gene) which might be related to protect against high-fat induced low grade inflammation [112].

Recently, small intestinal proteomes in weanling piglets that respond differently to probiotic (*Lactobacillus fermentum* I5007) and antibiotic (Aureomycin) supplementation in terms of lipid metabolism have shown that probiotic enhanced mucosal SAR1B abundance could prevent weanling piglets from fat malabsorption. More importantly, high mucosal abundance of EIF4A and KRT10 in probiotic-treated piglets may contribute to improve overall gut integrity, suggesting a potential reduction of LPS influx [113].
