This study was designed to compare the effects of dietary supplementation with nondigestible carbohydrates, differing in fermentability by colonic bacteria, on hepatic steatosis in growing obese Zucker rats. Male Zucker fa/fa rats were divided into three groups: a control group that received the basal diet, a fructan group that received 10 g highly fermented Synergy 1/100 g diet and a cellulose group that received 10 g poorly fermented Vivapur Microcrystalline cellulose/100 g diet. Rats consuming fructan had a lower energy intake, a lower body weight and less triacylglycerol accumulation in the liver as assessed in vivo by nuclear magnetic resonance (NMR) spectroscopy, and ex vivo by biochemical and histochemical analysis compared with the control and/or cellulose groups. The high fermentation of fructans compared with cellulose was reflected by greater cecal contents and by a twofold greater propionate concentration in the portal vein of rats fed fructan compared with those fed cellulose. By measuring the capacity of hepatocytes isolated from liver of Zucker rats to synthesize triglycerides or total lipids from different precursors, we showed that propionate, at the concentrations measured in the portal vein of rats treated with fructan, selectively decreased the incorporation of acetate into total lipids, a phenomenon that could contribute, along with the lower energy intake, to less triglyceride accumulation in the liver of obese Zucker rats fed dietary fructans.

Inulin and oligofructose, besides their effect on the gastro-intestinal tract, are also able to exert 'systemic' effect, namely by modifying the hepatic metabolism of lipids in several animal models. Feeding male Wistar rats on a carbohydrate-rich diet containing 10 % inulin or oligofructose significantly lowers serum triacylglycerol (TAG) and phospholipid concentrations. A lower hepatic lipogenesis, through a coordinate reduction of the activity and mRNA of lipogenic enzymes is a key event in the reduction of very low-density lipoprotein-TAG secretion by oligofructose. Oligofructose is also able to counteract triglyceride metabolism disorder occurring through dietary manipulation in animals, and sometimes independently on lipogenesis modulation: oligofructose reduces post-prandial triglyceridemia by 50 % and avoids the increase in serum free cholesterol level occurring in rats fed a Western-type high fat diet. Oligofructose protects rats against liver TAG accumulation (steatosis) induced by fructose, or occurring in obese Zucker fa/fa rats. The protective effect of dietary inulin and oligofructose on steatosis in animals, would be interesting, if confirmed in humans, since steatosis is one of the most frequent liver disorders, occurring together with the plurimetabolic syndrome, in overweight people. The panel of putative mediators of the systemic effects of inulin and oligofructose consists in either modifications in glucose/insulin homeostasis, the end-products of their colonic fermentation (i.e. propionate) reaching the liver by the portal vein, incretins and/or the availability of other nutrients. The identification of the key mediators of the systemic effects of inulin and oligofructose is the key to identify target function(s) (or dysfunction(s)), and finally individuals who would take an advantage of increasing their dietary intake.

We studied the influence of oligofructose (OFS), a nondigestible fructan, on lipid metabolism in obese fa/fa Zucker rats. The addition of 10 g/100 g OFS to the diet slowed the increase in body weight without modifying serum triglycerides or glucose concentrations after 7 wk of treatment. However, an oral load of 2 g glucose and 5 g corn oil/kg body weight increased triglyceridemia more in OFS-fed rats than in control rats. After 10 wk, OFS decreased the hepatic concentration of triglycerides 57% relative to controls. The less severe steatosis was confirmed by histologic analysis. Among the key enzymes involved in fatty acid synthesis and esterification, only malic enzyme activity was significantly lower in OFS-fed rats than in controls. The epididymal fat mass was significantly lower in OFS-fed rats. In conclusion, dietary enrichment with OFS can counteract both the fat mass development and the hepatic steatosis that occur in obese Zucker rats. Future studies will be designed to clarify in obese animals the influence of dietary OFS on postprandial triglyceridemia, which is an important variable associated with the development of atherosclerosis in humans, and to analyze the biochemical mechanism underlying the "hepatoprotective" effect of OFS.

In the past few years, scientific interest has focused on We quantitatively assessed rates of cell replication and the process of apoptosis. Like cell replication, apoptosis is of apoptosis during the development and regression of controlled by the networks of positive and negative growth liver cancer. In rats, apoptotic activity gradually insignals. 3,[6][7][8][9][10][11] Currently prevailing views assume that maligcreased from normal liver to putative preneoplastic foci nant cells are incapable of apoptosis and/or are not responsive (PPF), to hepatocellular adenoma (HCA), and to hepatoto death signals, thereby allowing unrestrained growth of cellular carcinoma (HCC). At all stages, rates of cell replicancer. cation were higher than of apoptosis, allowing a prefer-We studied the role of apoptosis for carcinogenesis and ential net gain of (pre)neoplastic cells. As in rats, in tumor reversion in rat and human liver. Liver cancer is human HCC, birth and death rates were increased maniamong the eight leading causes of cancer death worldwide; fold, indicating a species-independent phenomenon. Imtherapeutic possibilities are very limited and prognosis is plications of the increasing cell turnover were studied usually poor. 12 Etiologic factors include genotoxic agents such in rats using the administration and withdrawal of naas certain mycotoxins or hepatitis B virus, and numerous fenopin (NAF), a liver mitogen and nongenotoxic carcinnongenotoxic exposures, e.g., ethanol, cytotoxic and inflamogen. Prolonged NAF treatment enhanced cell number matory events, steroid hormones, as well as overnutrition, in normal liver by 25%, while PPF and liver tumors were dietary constituents and some drugs, all of which may enamplified at least 100-fold. After stopping NAF treathance the growth rate of precancerous and cancerous lesions ment, cell replication ceased, while cell elimination by in the liver. 12,13 Experimental results on cancer prestages apoptosis was increased in normal and (pre)neoplastic (putative preneoplastic foci [PPF]) in this organ were not liver. HCA and HCC showed the most pronounced shifts consistent with the concept of failure of apoptosis during carfrom replication toward apoptosis. As a result, 5 weeks cinogenesis. Rather, PPF showed rates of apoptosis much after halting NAF, 20% of cells in normal liver, but about higher than normal liver; thus, the high rate of cell replica-85% of (pre)neoplastic lesions including HCC, were elimtion in PPF was largely counteracted and net growth was inated. The implications of these findings include that impeded. 11,14,15 Tumor promotion by liver mitogens or overnongenotoxic carcinogens can act as survival factors feeding inhibited apoptosis and enhanced survival of cells even for malignant cells. Furthermore, tumor cells not preferentially in PPF, thereby allowing their selective only exhibit excessive proliferation, but also undergo growth; conversely, withdrawal of these survival/growth facapoptosis at rates that far exceed those in normal tissue.tors enhanced apopt...

Hepatocarcinoma cells (TLT) were incubated in the presence of ascorbate and menadione, either alone or in combination. Cell death was only observed when such compounds were added simultaneously, most probably due to hydrogen peroxide (H2O2) generated by ascorbate-driven menadione redox cycling. TLT cells were particularly sensitive to such an oxidative stress due to its poor antioxidant status. DNA strand breaks were induced by this association but this process did not correspond to oligosomal DNA fragmentation (a hallmark of cell death by apoptosis). Neither caspase-3-like DEVDase activity, nor processing of procaspase-3 and cleavage of poly(ADP-ribose) polymerase (PARP) were observed in the presence of ascorbate and menadione. Cell death induced by such an association was actively dependent on protein phosphorylation since it was totally prevented by preincubating cells with sodium orthovanadate, a tyrosine phosphatase inhibitor. Finally, while H2O2, when administered as a bolus, strongly enhances a constitutive basal NF-kappaB activity in TLT cells, their incubation in the presence of ascorbate and menadione results in a total abolition of such a constitutive activity.