Inhibition of matrix metalloproteinases increases PPAR-alpha and IL-6 and prevents dietary-induced hepatic steatosis and injury in a murine model.

Steatosis is a prominent feature of nonalcoholic fatty liver disease and a potential promoter of inflammation. Injury leading to cirrhosis is partly mediated by dysregulation of matrix protein turnover. Matrix metalloproteinase (MMP) inhibitors protect mice from lethal TNF-alpha induced liver injury. We hypothesized that Marimastat, a broad-spectrum MMP and TNF-alpha converting enzyme (TACE) inhibitor, might modulate this injury through interruption of inflammatory pathways. Triglyceride and phospholipid levels (liver, serum) and fatty acid profiles were used to assess essential fatty acid status and de novo lipogenesis as mechanisms for hepatic steatosis. Mice receiving a fat-free, high-carbohydrate diet (HCD) for 19 days developed severe fatty liver infiltration, demonstrated by histology, magnetic resonance spectroscopy, and elevated liver function tests. Animals receiving HCD plus Marimastat (HCD+MAR) were comparable to control animals. Increased tissue levels of peroxisome proliferator activated receptor-alpha (PPAR-alpha), higher levels of serum IL-6, and decreased levels of serum TNF-alpha receptor II were also seen in the HCD+MAR group compared with HCD-only. In addition, there was increased phosphorylation, and likely activation, of PPAR-alpha in the HCD+MAR group. PPAR-alpha is a transcription factor involved in beta-oxidation of fatty acids, and IL-6 is a hepatoprotective cytokine. Liver triglyceride levels were higher and serum triglyceride and phospholipid levels lower with HCD-only but improved with Marimastat treatment. HCD-only and HCD+MAR groups were essential fatty acid deficient and had elevated rates of de novo lipogenesis. We therefore conclude that Marimastat reduces liver triglyceride accumulation by increasing fat oxidation and/or liver clearance of triglycerides. This may be related to increased expression and activation of PPAR-alpha or IL-6, respectively.

Omega-3 fatty acids improve hepatic steatosis in a murine model: potential implications for the marginal steatotic liver donor.

The presence of nonalcoholic fatty liver disease often precludes potential organs from being used for transplantation. To date, there is no adequate treatment for hepatic steatosis, and it is expected that, because of increased obesity in Western society, the incidence of this disorder will increase. We investigated the effect of omega-3 polyunsaturated fatty acid supplementation on the treatment of hepatic steatosis in C57/Bl6 mice fed a high-carbohydrate, fat-free diet and in B6.V-Lep(ob) obese mice. Omega-3 fatty acid supplementation reversed hepatic steatosis in C57/Bl6 mice fed a high-carbohydrate, fat-free diet and converted macrovesicular to microvesicular steatosis in B6.V-Lep(ob) obese mice as determined by histology, magnetic resonance spectroscopy, and liver biochemistry We therefore conclude that omega-3 fatty acid supplementation improves hepatic steatosis in mice and may be used to increase the pool of potential live liver donors that are currently excluded because of the presence of macrovesicular steatosis.

Parietal dysfunction is associated with increased outcome-related decision-making in schizophrenia patients.

BACKGROUND: Decision-making is a complex process and depends on a network of fronto-parietal and cingulate areas. Decision-making dysfunctions in schizophrenia patients are characterized by an alternation between stereotypic and unpredictable responses. This study tested the hypothesis that schizophrenia patients show less decision-making-related activation in the prefrontal and parietal cortex. METHODS: Fifteen schizophrenia patients were matched with fifteen normal comparison subjects. During functional magnetic resonance imaging (fMRI) scanning, subjects were tested on the two-choice prediction task (predicting the location of a randomly presented stimulus) and the two-choice response task (responding according to the location of the stimulus). RESULTS: Schizophrenia patients relative to comparison subjects generated more outcome-dependent responses. Schizophrenia patients and normal comparison subjects showed decision-making-related activation in right prefrontal cortex, insula, anterior cingulate, and bilateral precuneus. Schizophrenia patients showed less activation in inferior, medial prefrontal, and right superior temporal cortex and more activation in the postcentral and inferior parietal cortex. Decision-making-related activation in both right prefrontal and bilateral parietal cortex was higher in medicated compared to unmedicated schizophrenia patients. CONCLUSIONS: These results support the hypothesis that the interaction between prefrontal and parietal cortex during decision-making by schizophrenia patients is dysregulated, which results in an increased outcome-dependent response selection.

Behavioral and functional neuroimaging evidence for prefrontal dysfunction in methamphetamine-dependent subjects.

Stimulant-dependent subjects show dysfunctions in decision-making similar to those seen in subjects with ventromedial prefrontal cortex lesions. Studies of drug craving, reward association, and decision-making have implicated dysfunctions of the dorsolateral and orbitofrontal cortex as a key neural substrate in subjects with stimulant dependence. Here, a functional magnetic resonance imaging (fMRI) study was carried out to determine the relationship between decision-making dysfunction and neural activation in different prefrontal areas. This investigation tested the behavioral hypothesis that methamphetamine-dependent subjects in early sustained remission show decision-making dysfunctions that are consistent with an increased reliance on stimulus-contingent response selection. It was hypothesized that these decision-making dysfunctions are due to differences in task-related activation in the dorsolateral and ventromedial prefrontal cortex. Ten methamphetamine-dependent subjects were compared with ten age- and education-matched controls performing a two-choice prediction task and a two-choice response task during a fMRI session. Response bias, latency, and mutual information measures assessing the underlying strategies of the decision-making sequences were obtained. First, methamphetamine-dependent subjects were more influenced by the immediately preceding outcome during the two-choice prediction task relative to normal comparison subjects. Second, methamphetamine-dependent subjects activated less dorsolateral prefrontal cortex (BA 9) and failed to activate ventromedial cortex (BA 10,11) during the two-choice prediction task compared with the two-choice response task. These results support the basic hypothesis that stimulant-dependent subjects exhibit fundamental cognitive deficits during decision-making that are consistent with both orbitofrontal and dorsolateral prefrontal dysfunction.