Earlier we have reviewed how obesity is assuming  an endemic/pandemic proportions resulting in escalating incidence as well as Prevalence associated escalating worldwide incidence of  Metabolic Syndrome (MetS) with Non alcoholic fatty liver disease (NAFLD) [1-7], that is  correlated with enhanced morbidity [8]. We tried to detail how probiotics, L-Carnitine (LC), Nicotinamide Ribose (NR) Combination ,along withApical Sodium Dependent Bile Acids Transporter (ASBT) or Volixibat and Silybin, Vitamin D, Allyl Isothiocyanate (AITC), might aid in treating  and understand the etiopathogenesis of NAFLD ,that was recently updated by Friedman etal. (figure1 as well as 2) [9]. Here we further update with regards to same. NAFLD encompasses a spectrum of disease from isolated hepatic steatosis(simple steatosis) to Non alcoholic steato hepatitis(NASH), that has  the properties of hepatocellular injury, inflammation, fibrosis in addition to finally results in  generation of cirrhosis  along with,  HCC[7,rev by us [10]. Simple steatosis constitutes relatively benign condition in addition to the pathological as well as      biological event of its evolution into NASH are complicated multiphasic [11]. Generation of   NAFLD implicates a lot of pathological events like fat collection, lipotoxicity, inflammation, Oxidative stress (OS) along with mitochondrial impairment [12]. High fat diet (HFD), feeding is a recognized etiology of liver steatosis as well as inflammation in experimental mice with clear cut Oxidative injury in the liver [13]. Mice fed a HFD for12-16 wks can reproduce the histopathological examination (HPE) as well as the pathological   injury properties of NAFLD [14]. Fat collection in the liver occurs secondary to the escalated uptake of circulating lipids, escalated nascent lipid generation in addition to    dysfunctional fatty acids (FA), Oxidation [15]. A lot of studies demonstrated that saturated FA, Part palmitic acid (PA), maximum free fatty acids (FFA) in diet serum that can in   liver fat as well as insulin resistance (IR). In addition these FFA can stimulate ER Stress as well as exaggerate mitochondrial metabolism [16]. Furthermore the collection of reactive oxygen species (ROS) facilitate liver cell impairment in addition to cell apoptosis [17]. Mitochondrial abnormalities along with, Oxidative stress are the core of the etiopathogenesis of NAFLD as per certain studies [18]. ROS might get generated by FFA  Oxidation in peroxisomes as well as microsomes  in addition to  macrophages stimulation [19]. ROS can result in cell injury by destruction of various bioenergetic responses implicated in Oxidative phosphorylation as well as stimulate a vicious cycle of oxidative injury [20]. In liver cells, mitochondrial impairment might exaggerate apoptotic signals ,depolarization of mitochondrial membrane, Oxidative phosphorylation as well as ATP loss [21]. Hence liver cells  can’t sustain  structural as well as functional   integrity  in addition  to start pro apoptotic signals along with mitochondrial processes, that  are influenced by  Bcl-2 family  protein(B cell lymphoma )  in addition to   pro apoptotic Bax (Bcl-2   associated  X   protein ) [22]. Alongwith

The innate immune response is the major determinant of inflammation as well as other pathological presentations of NAFLD [rev by us in ref 6,7]. Bone marrow (BM) -obtained macrophages that have been recruited represent a crucial  factor in acute as well as chronic  hepatitis  in addition to inflammatory microenvironment  possessing lipopolysaccharides (LPS) along with palmitate => macrophage polarization   to the proinflammatory M1 type ,that generates inflammatory cytokines for sustainance of inflammation as well as can facilitate fibrosis  by liberation of fibrotic cytokines [23]. Additionally, 5-lipoxygenase (5LO) is basically expressed in inflammatory cells, that include monocytes, mast cells as well as B lymphocytes [24]. In the liver macrophage are the only area where 5LO gets metabolised [25].

A lot of studies have verified the association among 5LOmetabolic pathway in addition to NASH [26]. Martinez-Clemente et al.’s study demonstrated in hyperlipidemia model of NAFLD in mice, Apo E-/-mice  where 5LO was absent demonstrated diminished liver inflammation in addition to macrophages infiltration as well as decreased caspase -3 along with nuclear factor κ(NFκB)  actions in addition to the expression of proinflammatory cytokines was decreased [27]. In toto these observations pointed that the 5LO pathway possesses a crucial part in the propagation of NAFLD.

Traditional Chinese medicine has got utilized for therapy of hepatic disease with minimal adverse actions for over a millennium [28]. AstragalosideIV (ASIV), is the active  ingredient of Astragalus ,that represents a commonly utilized Chinese medicine, with established pharmacologic actions  like anti Oxidative stress,anti-inflammatory,anti apoptosis in addition to anti fibrotic  actions[29].It has been documented that ASIV decreases PA—stimulated lipid collection along with endoplasmic reticulum (ER) stress  in hepatocytres[30].Proof that is being displayed that  ASIV   decreases liver injury by decreasing Oxidative stress as well as inflammation [31]. Nevertheless,  the actions  of ASIV on NAFLD in addition to its underlying mode  are not clear. Thus Liang et al. [32], tried to evaluate pharmacologic AstragalosideIV(ASIV),that has been tested in experimental models of a variety of diseases, fortheir action along with mode of action as well as      how it confers protection   in NAFLD.LPS along with Palmitate acid (PA)- stimulated RAW 264.7 cells in addition to  LO2 cells in the form of a NAFLD model. The mice NAFLD model got analysed  by Haematoxylin as well as  Eosin staining ,along with aspartate   transferase (AST ) as well as alanine transferase(ALT) amount. Lipid metabolism of liver was investigated  by total triglycerides(TG) along with  total cholesterol(TC)kits along with oil red O  Staining. Indicators of Oxidative stress were examined  via biochemical assays. Whereas inflammatory factors got evaluated via ELISA, RT-quantitative PCR as well as   OS indicator kits. The expression amount of 5LO as well as leukotriene A4 hydrolase (LTA4H) got examined via RT-quantitative PCR as well as western blotting. For checking apoptosis, Annexin V –FITC/PI Cell apoptosis detection kit.Their  outcomes  demonstrated that in vivo ASIV  significantly  decreased liver   tissue ,besides serum AST, ALT in addition to serum TG amount  in NAFLD mice. In vitro ASIV hampered the  cell supernatant  TG along with amount hTC   via PA therapy.  in addition ASIV   decreased biological reactive oxygen species(ROS) along with malondialdehyde (MDA) amounts ,besides resurrecting glutathione peroxidase(GSH-Px) amounts in LO2 cell supernatant. They also observed ASIV hampered the generation  of proinflammatory  cytokines (Tumor necrosis factor alpha(TNFα)  as well as interleukin -6) in RAW 264.7 cells stimulated by LPS.  Moreover ASIV downregulated the expression of 5LO along with LTA4 B4(leukotriene B4) in NAFLD mice. They also found that  ASIVresurrected pro apoptotic protein  ( Bax as well as Bcl-2) expression in PA-treated LO2 cell.Thus concluding  that  ASIV might aid in reduction of hepatic steatosis, hepatocyte Oxidative in addition to decrease of liver inflammation, thus amelioration of propagation of  NAFLD, hence it is  significant therapeutically [32].

Conclusions -To summarize targets for treatment might be liver particular as per figure2 in mode of action for targets or extra hepatic. Additionally, besides these liver- particular targets, extrahepatic targets are the microbiome and gut–liver signaling axis [as reviewed by us in ref 3,4  as well as other organs that contribute to MetS, especially muscle and adipose tissue. Besides using NR, LC Combination, Volixibat,AITC ,these newer agents like extracts from TCM, ASIV, drugs for reduction in BMI etc.

Legend for Fig. 2|

Intrahepatic drug targets in phase 2 and 3 clinical trials for NASH.

Courtesy ref no-9-Depiction of the sites of action of drugs that are currently in phase 2 or 3 clinical trials, based on their primary locus of activity within the liver. Targets include those that regulate lipids and glucose homeostasis, and oxidant stress and mitochondrial targets in hepatocytes, inflammatory signals converge on hepatocytes, and those inflammatory signals and intracellular targets related to stellate cell activation andfibrogenesis. Gray boxes indicate disease drivers. Some targets (e.g, FXR agonists, CCR2 and CCR5 (CCR2/5) antagonist) have more than one action within the injury milieu. Agonists are indicated with a circle and antagonists with a cross. DGAT, Diacylglycerol O-acyltransferase; SCD, steroyl CoA-desaturase; THR, thyroid hormone receptor; SIRT, sirtuin; GLP, glucagon-like peptide; SGLT, sodium–glucose cotransporter; VAP, vascular adhesion protein; LPS, lipopolysaccharide; PPARα/δ/γ, peroxisome proliferator–activated receptors PPARα, PPARδ and PPARγ

Although activity in drug development for NASH is intense and advancing rapidly, it is the  opinion, of Friedman etal.[8], it is  too early to prioritize those drugs or mechanisms that are most promising, as clinical trials thus far have been relatively short (3–18 months), whereas any approved therapies will likely be administered long-term. Thus, although the efficacies of several agents in clinical trials, such as an FXR agonist (obeticholic acid), a PPARα and PPARδ agonist (elafibrinor) along with  a CCR2  in addition to  CCR5 antagonist (cencriviroc), are promising  depending  on liver biopsy or noninvasive biomarkers, these findings would need  translatiom  into durable safety and efficacy. Moreover, the possibility of drug combinations as a future therapeutic option is increasingly likely because of concern that attacking a single target will not be sufficiently potent, but there is no data yet from long-term, controlled trials hence results from long term studies are awaited to ensure prevention of cirrhosis, HCC in this dreaded disease. .