Children of women who consume a high-fat diet during pregnancy and lactation have an increased risk of lifelong obesity and related metabolic disorders compared to children of women who consume healthy diets, says a new study by researchers at the Yale School of Medicine and the University of Cologne as published in the journal Cell. Using a rodent model, the researchers fed mice either a normal diet or a high-fat diet for eight weeks prior to pregnancy. The researchers discovered that the offspring of the mother mice who only had a high-fat diet when nursing showed the biggest affects of the diet change in terms of body weight and increased body fat content.
Previous studies have discovered a link between maternal obesity and an increased risk of obesity and other health issues in the offspring of obese mothers. The present study suggests that maternal diet can affect the health of offspring before, during, and after pregnancy. The results of the present study can help identify the key point in pregnancy when maternal nutrition has the most impact on the metabolic health of offspring.
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Increased prevalence of non-alcoholic fatty liver disease (NAFLD) is one of the consequences of the current obesity epidemic. Mechanisms of extra-hepatic perturbations in non-alcoholic fatty liver disease (NAFLD) progression. TLR4-mediated signaling can activate the hepatic pro-inflammatory nuclear factor-?B (NF-?B) signaling cascade to induced hepatic inflammation and oncogenic interleukin 6 (IL-6)-signal transducer and activator of transcription 3 (STAT3) pathway [44,45]. Mechanisms of intra-hepatic perturbations in non-alcoholic fatty liver disease (NAFLD) progression.
Most notably, high-fat maternal diets during breastfeeding can alter metabolism and increase the risk of obesity in offspring.
These offspring had abnormal neuronal connections in the hypothalamus and altered insulin signaling in this brain circuit.
NAFLD is a major form of chronic liver disease that is highly prevalent in obese and overweight adults and children. IntroductionLiver cancer is the third leading cause of cancer-related deaths worldwide [1,2,3], and the most frequent and aggressive primary liver tumor is hepatocellular carcinoma (HCC) [1,2,3]. Detail mechanistic activation of NF-?B signaling and subsequent pro-inflammatory response in liver diseases has recently been reviewed [7,46].
Increase in dietary lipids elevates triglyceride (TAG) and cholesterol delivery to the liver by chylomicrons (CM) and CM remnants (Rem.).
ROS and CYP-P450 EnzymesFA oxidation occurs within mitochondria, peroxisomes and the ER [93,94].
Both of these changes resulted in obesity and abnormalities in glucose metabolism throughout life. He has worked for both Thomas Edison and Nikola Tesla and along the way becomes involved with the governmenta€™s secret World War Two project a€?The Philadelphia Experimenta€™ dealing with time travel. Nonalcoholic steatohepatitis (NASH) is the severe form of NAFLD, and uncontrolled inflammation as displayed in NASH has been identified as one of the key events in enhancing hepatic carcinogenesis. Prevalence of HCC is twice as high in males as in females, with very limited treatment options, and almost universally fatal within a year unless detected early [1,4].
Circulatory LPS can stimulate proinflammatory cytokine secretion by macrophages (M?) and adipocytes through toll-like receptor (TLR)-4-mediated signaling. Inflammasomes are a group of intracellular multimeric protein complexes that mediate autoactivation of caspase 1 when activated by endotoxin and other particles that have surface expression of foreign epitopes [43]. ?-Oxidation that occurs in the mitochondria is effective in generating cellular energy, and maintaining lipid homeostasis [93,94].
Lycopene is a non-provitamin A carotenoid and the pigment principally responsible for the characteristic deep-red color of ripe tomato and tomato products, as well as some fruits and vegetables. Despite the gradual decline in all cancer incidences, HCC still tops the lists of cancers with increasing morbidity and mortality trends in the United States [1,4], with its prevalence doubled between 1983 and 2002 [5,6]. LPS can also act on Kupffer cells (KCs) and hepatic stellate cells (HSCs) via TLR4 signaling to promote hepatic inflammation and fibrogenesis. Activation of caspase 1 by cleavage results in the maturation and secretion of the pro-inflammatory cytokines IL-1? and IL-18, leading to hepatic inflammation. Unlike short- or median-chain FAs, long-chain FAs (LCFA) in the cytosol require carnitine palmitoyltransferase-1 (CPT-1) for their translocation into the mitochondria [93,94].
Half of the mother mice fed a normal diet during pregnancy were fed a high-fat diet during lactation, and half of the mother mice fed a high-fat diet during pregnancy were fed a normal diet during lactation.

Lycopene’s innate antioxidant and anti-inflammatory properties have generated research interests on its capacity to protect against human diseases that are associated with oxidative stress and inflammation.
The risk for developing HCC is influenced by environmental factors, including viral induced hepatitis, alcohol consumption, and a recently defined factor, obesity [7]. Hepatic inflammation activates hepatocytes secrete fetuin A (FetA) into systemic circulation. Caspase 1 activation can also inactivate sirtuin 1 (SIRT1) by cleavage [47], where SIRT1 is a NAD+-dependent protein deacetylase with anti-inflammatory properties [48,49,50,51,52], and it is recognized to protect against obesity-induced hepatic steatosis and inflammation [48,53,54,55,56].
Accumulation of ceramide can disrupt mitochondrial function and induce reactive oxygen species (ROS) production, which subsequently leads to hepatic inflammation. Malonyl-CoA, an early intermediate of DNL synthesized by ACC, is an allosteric inhibitor of CPT-1 [120], thus elevated DNL can inhibit FA ?-oxidation and promote excess hepatic lipids in NAFLD [121].
In addition, differential mechanisms of lycopene metabolism including endogenous cleavage by carotenoid cleavage oxygenases (BCOs), generate lycopene metabolites that may also have significant impact on human disease development. HCC’s escalating morbidity and mortality trends parallel to the rising prevalence of non-alcoholic fatty liver disease (NAFLD), a chronic liver disease that is observed in 75%–100% of overweight and obese adults and children [8,9,10], and describes a range of related disorders that can progress in stages [11].The earliest stage of NAFLD is hepatic steatosis, or lipids deposition in the cytoplasm of hepatocytes [10,11]. Metabolic surplus stimulates adipocyte hypertrophy and the subsequent systemic release of free fatty acids (FFA). IL-1? expression has recently been shown in mice to promote senescence-associated secretory phenotype (SASP) in hepatic stellate cells that facilitates chemical carcinogen-induced HCC development [57]. Excess hepatic long-chain FA (LCFA) can undergo ?-oxidation in the endoplasmic reticulum (ER), and result in generation of ROS. Hepatic lipid overload can also promote LCFA ?-oxidation that occurs in the ER and induce the generation of ROS (Figure 2) [122], which is a key factor for NASH progression from steatosis [123].ROS are toxic to macromolecules (lipids, proteins, RNA and DNA), and may facilitate cancer initiation [123]. However, it remains to be elucidated as to whether lycopene or its metabolites apolycopenoids have protective effects against obesity-related complications including inflammation and tumorigenesis. Hepatic steatosis can progress to the more aggressive form of NAFLD called nonalcoholic steatohepatitis (NASH) [8,10]. Circulatory FFA can associate with FetA released from the liver and activate TLR4-mediated proinflammatory signaling in adipocyte and M?, creating a feed-forward mechanism in promoting further systemic and hepatic inflammation. Dysregulation in the balance between ROS generation and removal will lead to oxidative stress, which promotes inflammation, apoptosis and necrosis [123]. This article summarizes the in vivo experiments that elucidated molecular mechanisms associated with obesity-related hepatic inflammation and carcinogenesis.
NASH is distinguished by the presence of hepatocyte injury (hepatocyte ballooning and cell death), infiltration of inflammatory cells, and may display collagen deposition [8,11].
Elevated dietary sugars can stimulate de novo lipogenesis (DNL) to generate FA, and stimulate ER stress-mediated unfolded protein response (UPR), leading to hepatic inflammation. This review also provides an overview of lycopene metabolism, and the molecular pathways involved in the potential beneficial properties of lycopene and apolycopenoids. NASH patients as compared to those with simple steatosis have a much greater risk for developing liver cirrhosis, a significant risk factor for HCC development [7].
The increased CYP-P450 protein expression and activity have been observed in obesity and NAFLD in both humans and rodents [124].
More research is clearly needed to fully unravel the importance of BCOs in tomato carotenoid metabolism and the consequence on human health and diseases. Robust evidence suggests that NAFLD progression from steatosis to NASH and HCC involves a multi-step process, from liver damage initiation, followed by inflammation, cycles of necrosis, and regeneration [7].
Hepatic inflammation and injury in NASH are effective in activating hepatic stellate cells, which are specialized cells that involve in liver regeneration, but they can also promote cirrhosis by replacing hepatocytes with type I collagen-rich scar tissue [7,11].
The main role of CYP-P450 protein in the liver includes the metabolism of xenobiotics (drugs, toxins, carcinogens) and endogenous substrates (FAs and steroids) [123,124].
This event results in an environment that is permissive to genetic modulations and exogenous impacts leading to neoplastic transformation [7,12]. CYP2E1 is a CYP-P450 enzyme that is mainly expressed in the liver, highest in hepatocytes, and has been identified as one of the relevant risk factors in NAFLD pathology [123,124,125].
Negativenegative feedback loops operate to maintain a thermostatically controlled atmospheric homeostasis with.
HCC has extraordinary heterogeneity of genomic aberrations [13], but more than 90% of HCC develops based on chronic inflammation as displayed in NASH [13].
CYP2E1 overexpression in a transgenic mouse model induced hepatic steatosis and injury [126], whereas application of CYP2E1 antibody inhibited hepatic lipid peroxidation in murine NASH model [127]. Such evidence highlights the critical role of hepatic inflammation in NAFLD associated hepatocarcinogenesis.Approximately 30%–40% of HCC patients in the US have NAFLD [6]. Further, Cyp2e1 knockout mice are protected from HFD-induced insulin resistance [128,129], providing evidence to suggest that CYP2E1 does play a role in NAFLD progression and metabolic syndrome. These individuals incidentally have high prevalence for metabolic syndromes including obesity and type II diabetes mellitus [14], suggesting a strong association between metabolic syndrome, NAFLD and HCC development. The escalating obesity prevalence in both adults and children is a serious global public health concern [15], and accumulating epidemiological evidence support the positive association between obesity and HCC risk [16,17,18,19]. Two other population-based cohort studies from Sweden and Denmark yield similar conclusions [6].
Obesity is associated with a state of chronic low-grade inflammation that can induce hepatic inflammation, and can potentially play a role in NAFLD progression [7,12,17,18,20].While targeting the root cause of metabolic syndrome including obesity may present the most effective prevention against NAFLD and HCC, it has been observed that caloric restriction on diet-induced obese mice was not effective in reversing the obesity-promoted tumorigenesis and associated signaling [21].
Therefore, potentially effective dietary preventions against this obesity-promoted tumorigenesis warrant investigation in easing public health burden.
This review summarizes the recent data on the molecular mechanisms interconnecting metabolic syndrome, chronic inflammation, and HCC progression. This article also presents the accumulated evidence on how lycopene and its metabolites apolycopenoids may attenuate metabolic syndrome-associated hepatic injuries and HCC progression. Other Systemic PerturbationsElevated expressions of circulatory growth hormone and factors including insulin and IGFs have been associated with metabolic syndrome [78,79].

The signal transduction networks of insulin and IGFs both play critical roles in promoting neoplasia in various tissues, whereas circulatory IGF-binding proteins (IGFBPs) attenuate the bioactivities of IGFs [78,79]. Insulin and IGFs can mediate mitogenic signaling through receptor-mediated mechanisms, thereby activating Ras-MAPK and the phosphatidylinositol 3-kinase (PI3K) and Akt pathways [78,79].
These pathways are important regulators of mammalian cell proliferation and survival, and are often dysregulated in human cancers [78,79]. Some epidemiological studies have observed higher systemic IGF1 and IGF2 in obese individuals with T2DM [67,68]. However, obesity also reduces the release of growth hormone that controls hepatic IGF synthesis [69].
The association between IGF and BMI from the European Prospective Investigation into Cancer and Nutrition (EPIC) study was non-linear, where those with a BMI of 26–27 had the highest circulatory IGF1 concentration [80]. GI TractConsumption of high fat diets (HFD) can promote hepatic inflammation by disrupting the intestinal barrier, thereby allowing increased translocation of bacteria and related antigens into the systemic circulation (Figure 1) [22,23,24,25,26,27].
However, a linear negative association between IGFBP1 and BMI was observed [80], suggesting that dietary components that induce IGFBP expression may still be effective in reverting oncogenic effects of IGFs.Other hallmarks associated with NAFLD are systemic lipid markers that are also risk factors of atherosclerosis, including elevated triglyceride (TG), cholesterol (CHOL), low density lipoprotein (LDL) and oxidative stress [81]. Liver receives a unique blood supply via the portal system connecting itself to the GI tract, exposing liver cells to nutrients as well as bacterial components that are translocated [28]. The elevated LDL in the presences of oxidative stress can result in the increased presences of oxidized LDL (oxLDL) [81].
Intestinal disruption can elevate portal endotoxemia by up to three-fold in healthy individuals on HFD [32], and 6 to 20-fold in individuals with NAFLD [33].
Under physiological conditions, myeloid cells including macrophages can internalize excess lipoprotein-derived cholesterol by receptor-mediated systems [82,83].
Tomato EffectsObservational and clinical studies have shown that dietary intake of tomatoes is associated with reduced risk for human cancers at numerous sites as reviewed previously [135,136,137], and this association remains to be explored with liver cancer.
Portal endotoxemia can sensitize hepatic stellate cells and resident macrophages called Kupffer cells (KCs) to bacterial endotoxins including lipopolysaccharides (LPS), leading to liver fibrosis and cirrhosis (Figure 1) [34,35,36,37,38,39,40,41]. When LDL becomes highly oxidized, these particles may display structures that are similar to pathogen-associated epitopes that increases their uptake by macrophages, partially through scavenger receptors A (SR-A) and CD36 [84]. However, results yielded from epidemiological studies are often difficult to conclude whether the observed chemopreventative effects are tomato or lycopene-dependent. The potential mechanisms involved include endotoxin-mediated activation of toll-like receptor (TLR) 4 pro-inflammatory signaling [35,42], and the innate immune signaling complex called the inflammasomes (Figure 1) [43]. Internalization of these oxLDL by macrophages has been postulated to accumulate in the lysosomal compartment due to poor degradation, leading to presence of cholesterol crystals [81,85,86]. The presence of these internal cholesterol crystals, along with oxidation-specific epitopes of LDL can be seen as damaged associated molecular patterns (DAMPs) and can activate the inflammasomes [87].
Clinical trials have been conducted to examine the effects of tomato products and lycopene containing supplements on various cancers [135,136]. Apart from stimulating the inflammasome, accumulation of oxLDL-derived cholesterol can also induce the activation of NF-?B signaling [88,89]. Similar to epidemiological studies, the clinical studies that utilized tomato products, as well as lycopene-containing supplements that often contain other phytonutrients (phytoene, phytofluene, ?-carotene, and tocopherols), are difficult to isolate lycopene’s beneficial effects.
These described oxLDL-stimulated pro-inflammatory effects are well-documented on circulatory macrophages, but emerging evidence have provided support that similar events do occur in KCs [85]. Therefore, human interventions and animal studies that compare the effects between isolated lycopene and the whole food tomato are essential in differentiating their potential beneficial effects against liver diseases. Isolated KCs from mice with early NASH has been shown to predominately accumulate cholesterol and cholesterol crystals specifically in the lysosomes, and displayed pro-inflammatory phenotypes [85,86,90]. Tomatoes by definition provide a high source of vitamin A and C, but they also consist of phytochemical including carotenoids and flavonoids. Hepatic inflammation observed in these mice was associated with the increased cholesterol storage inside lysosomes of KCs [86,91]. Lycopene is the most abundant carotenoid found in tomato, tomato products and other red fruits, and these food products have also been shown to contain lycopene metabolites [138]. Intravenous injection of oxLDL for 2 weeks induced severe hepatic inflammation as displayed in NASH in mice fed HFD for 23 weeks, as compared to PBS injected HFD-fed mice [92].
With respect to liver diseases, we have previously shown that tomato extract supplementation was more protective against HFD-induced hepatic inflammation than lycopene [139]. Clearly, further investigations are needed to examine whether nutrients in tomatoes may work additively or synergistically in protecting against liver diseases. It remains to be elucidated as to whether oxLDL-induced hepatic inflammation stems mainly from affected circulatory macrophages or KCs. ER StressElevated synthesis of lipogenic enzymes demands excess work of the endoplasmic reticulum (ER) for proper protein folding [112,113,114], hereby inducing ER-stress.
Hepatic DNL has been impeded in promoting hepatic inflammation through activation of ER stress-mediated unfolded protein response (UPR; Figure 2) [112,113,114].
UPR consists of three distinct pathways regulated by ER membrane-bound proteins: inositol requiring (IRE) 1?-X-box binding protein 1 (XBP1) system, PKR-like ER kinase (PERK)-eukaryotic initiation factor (eIF) 2? signaling, and activating transcription factor (ATF) 6? [112,113,114]. Activation of the PERK and IRE1 pathways can promote NF-?B mediated pro-inflammatory response, whereas PERK-signaling in tumors can promote cellular growth through activation of Akt [116,117,118]. ER stress can also exacerbate lipid accumulation by activating lipogenesis through SREBP-1c [119], creating a vicious cycle to sustain the pro-inflammatory state.

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