**3. LPS modulation of Sirt1/p53 interactions is coupled to fat ingestion, dysfunction of the immune system, and metabolic liver disease**

Underneath, a high-stringency emulation (using the Mir@nt@n algorithm), and based on the most recent scientific articles [86–90], the links between microRNA species and genes shown to be implicated in the development of the "fat liver syndrome" are shown in **Figures 1** and **2**,

Suffice to say, SIRT1, seems to be modulated by hsa-mir-30c, while, ABCA1-levels are determined by the integrated input of signals emanating from micro-RNA species like hsa-MiRs 144, 148a, 145, and 33b. Future studies of these MiRs will show whether they might be targets or markers for gene manipulations normalizing liver metabolism, and thus combatting adiposity,

**Figure 1.** High stringency emulation of gene-microRNA interactions, showing the impact of microRNA species on some "master" genes involved in the development of supersized adipocytes with the WAT (white adipocyte tissue-phenotype)

**Figure 2.** High stringency emulation of gene-microRNA interactions, showing the impact of microRNA species on some "master" genes involved in the development of a fatty liver in patients developing nonalcoholic fatty liver disease

in patients with aberrant lipid metabolism and/or adiposity.

alongside a fatty liver in patients developing nonalcoholic fatty liver disease (NAFLD).

respectively.

8 Adiposity - Omics and Molecular Understanding

(NAFLD).

The immune-based hypotheses involve the aberrant regulation of Sirt1/p53 and a lack of adaptation to the environment, which implicates an abnormally functioning immune system in both the pathogenesis of insulin resistance and aging [85, 86]. Diets, which are high in fat and low in fibrous compounds, are linked to an enhancement of gut microbiota in the circulation, with impact on immune functions, lowered insulin sensitivity, as well as energy homeostasis in both animals and humans [77–83]. Noteworthy, animals fed a high fat/cholesterol diet demonstrated enhanced levels of bacterial endotoxins (known as lipopolysaccharides, LPS) with a parallel enhancement of inflammatory processes [64–66]. In this respect, both LPS and cytokines have been associated with enhanced hepatic sphingolipid synthesis with altered ceramide contents, which has been associated with peripheral insulin resistance. In obese mice, a change in inflammatory responsiveness was demonstrated subsequent to LPS administration [9, 10], followed by an alteration in intestinal microbiota and NAFLD, known to be closely correlated with systemic inflammation and the metabolic syndrome [11–16]. Hence, it was shown (verified) that the immune system is involved in the crosstalk between adipose tissue and liver, which inevitably implicates bacterial toxins in the pathogenesis and further development of NAFLD and obesity.

The LPSs are dimeric polysaccharide moieties linked to a lipid core, anchored within the cell membrane [18, 19], and have been shown to effect hepatic genomic stability [20] affecting reverse cholesterol transport (RCT) in macrophages by downregulation PPARγ [21–30]. LPSs have demonstrated to directly affect mitochondrial DNA synthesis linked to mitochondrial dysfunction [31]. LPSs are also involved in adipocyte-macrophage intercommunication, enhancing systemic inflammatory responses [32], being linked to DNA damage [33]. LPS and fat absorption have received increased interest, related to their effects on the Sirt1-mediated modulation of hepatic cholesterol homeostasis, as well as their impact on β-amyloid metabolism [34].

LPS-binding proteins (LBPs) associate with LPS and alter inflammatory responses [35]. The LBPs, as well as leptin, are both upregulated in the obese, impinging on biological phenomena, like the expression of leptin, appetite, and obesity-provoked inflammatory reactions [36–40]. LPS has, since long, been demonstrated to affect the efflux of cholesterol via the liver X Receptors (LXR) and the ATP-binding cassette transporter 1 (ABCA1) [41, 42] pathways, of which the latter is overriding the Sirt1-mediated impact on LXR-ABCA1 interactions. A lowering of the ingestion of fat [35] suppresses plasma LPS levels, and has therefore become a strong tool in the reduction of both the development and impact of metabolic diseases on health in general. LPS has been shown to modulate SREBP expression in macrophages, while also subduing liver PGC1α expression [29, 42, 43], and thus being associated with an abnormal Sirt1-regulation of basal adipocyte cell functioning [27, 44]. The LPS-facilitated "blockage" of the elimination of cholesterol from macrophages has been demonstrated to serve as an important factor in the cholesterol-rich lipoprotein intercommunication network [45–47], thus impacting on LPS neutralization in metabolic diseases, with focus on diabetes [48–50].

LPS-induced production of interferon-gamma (IFγ) has been shown in both NK-cells and T- lymphocytes impacting genes encoding inflammatory cytokines, glucose metabolism, and macrophage-related modulation of genes in adipocytes [51, 52]. IFγ has also been shown to affect genes, like Sirt1 and p53 apoptosis coupled genes, whose role are being "dissociated" in dysfunctional stages of metabolism [45–53]. The impact of IFγ on chromatin modeling stimulates macrophages, controlling gene transcription, thus regulating inflammatory cytokine production in activated macrophages [46, 47]. In this context, MiR-34a and other MiRs are involved in the modulation of the IFγ-mediated innate immune responses [48, 49]. However, one has discovered an inverse correlation between adiponectin and inflammatory cytokines, with adiponectin levels being associated with NK-cell activation [50–52].

The LPS-stimulated biological effect on p53-induced apoptosis in the liver [53, 54] surpasses the effect of Sirt1 as to the deacetylation of p53, reducing the hepatic lipid turnover. Hence, the p53-mediated downregulation of PXR activity [55, 56] is not dependent of the Sirt1/PXR-mediated reactions [57–60]. Therefore, the untoward p53/PXR interactions, which lead to NAFLD, are coupled to an altered expression of miRNA species related to the turnover of xenobiotics [61–63]. In this context, xenobiotic metabolism has been shown to be disturbed in obese individuals, which is associated with enhanced lipid synthesis [63], disturbed immune reactions [62], and marked apoptosis [64, 65]. The high levels of phthalates contained within alimentary like milk, butter, and meats are linked to the Sirt1/ p53 interactions [66–68], which couples the phthalates to NAFLD and adiposity in communities worldwide [68].

Furthermore, the focus on α-synuclein and its impact on the immune system in the periphery [69, 70] and CNS [71, 72] have emerged as knowledge about its regulatory impact on p53 transcriptional regulation of apoptosis has increased. Sirt1-mediated effects on hepatic α-synuclein and amyloid-β turnover are closely linked to LPS [72], metabolic diseases, as well as obesity, with observed impact on p53 transcriptional regulation by both α-synuclein and amyloid-β metabolism in the liver and brain [73–77].
