Peroxisome proliferator-activated receptor alpha mediates the adaptive response to fasting.
(9/3223)
Prolonged deprivation of food induces dramatic changes in mammalian metabolism, including the release of large amounts of fatty acids from the adipose tissue, followed by their oxidation in the liver. The nuclear receptor known as peroxisome proliferator-activated receptor alpha (PPARalpha) was found to play a role in regulating mitochondrial and peroxisomal fatty acid oxidation, suggesting that PPARalpha may be involved in the transcriptional response to fasting. To investigate this possibility, PPARalpha-null mice were subjected to a high fat diet or to fasting, and their responses were compared with those of wild-type mice. PPARalpha-null mice chronically fed a high fat diet showed a massive accumulation of lipid in their livers. A similar phenotype was noted in PPARalpha-null mice fasted for 24 hours, who also displayed severe hypoglycemia, hypoketonemia, hypothermia, and elevated plasma free fatty acid levels, indicating a dramatic inhibition of fatty acid uptake and oxidation. It is shown that to accommodate the increased requirement for hepatic fatty acid oxidation, PPARalpha mRNA is induced during fasting in wild-type mice. The data indicate that PPARalpha plays a pivotal role in the management of energy stores during fasting. By modulating gene expression, PPARalpha stimulates hepatic fatty acid oxidation to supply substrates that can be metabolized by other tissues. (+info)
Effectiveness of the analogue of natural Schisandrin C (HpPro) in treatment of liver diseases: an experience in Indonesian patients.
(10/3223)
OBJECTIVE: To determine the effect of dimethyl-4,4'-dimethoxy-5,6, 5',6-dimethylene dioxybiphenyl-2,2'-dicarboxylate (HpPro) on patients with acute and chronic liver diseases. METHODS: An open trial and a prospective randomized and controlled study were performed. The open trial consisted of 56 cases (16 cases of acute hepatitis, 20 cases of chronic hepatitis, 14 cases of liver cirrhosis and 6 cases of fatty liver). Controlled study consisted of 20 cases of Child A chronic hepatitis which were randomly treated with either HpPro or a mixture of known drugs which used as a liver protective agent in Indonesia as control for one week. The patients were then crossed over those two drugs in the next week. RESULTS: In the open trial, after 4 weeks' treatment with HpPro 7.5 mg orally three times daily, acute hepatitis, chronic hepatitis and fatty liver cases showed rapid decrease of SGOT and SGPT. In the liver cirrhosis cases, SGOT and SGPT were decreased slowly. In the controlled trial, nine patients received HpPro 7.5 mg three times daily orally and eleven were treated with a mixture of known drugs as the controls. After one week treatment, HpPro group clinically showed significant decrease of SGPT and SGOT levels compared to control group (P = 0.035). At the second week, HpPro group showed significant decrease of SGOT compared to control group (P = 0.038) but the decrease of SGPT was not significant (P = 0.096). CONCLUSION: Treatment with HpPro is effective to reduce liver impairment in acute and chronic liver diseases on Indonesian patients. No side effect of HpPro was observed. (+info)
Peroxisomal and mitochondrial fatty acid beta-oxidation in mice nullizygous for both peroxisome proliferator-activated receptor alpha and peroxisomal fatty acyl-CoA oxidase. Genotype correlation with fatty liver phenotype.
(11/3223)
Fatty acid beta-oxidation occurs in both mitochondria and peroxisomes. Long chain fatty acids are also metabolized by the cytochrome P450 CYP4A omega-oxidation enzymes to toxic dicarboxylic acids (DCAs) that serve as substrates for peroxisomal beta-oxidation. Synthetic peroxisome proliferators interact with peroxisome proliferator activated receptor alpha (PPARalpha) to transcriptionally activate genes that participate in peroxisomal, microsomal, and mitochondrial fatty acid oxidation. Mice lacking PPARalpha (PPARalpha-/-) fail to respond to the inductive effects of peroxisome proliferators, whereas those lacking fatty acyl-CoA oxidase (AOX-/-), the first enzyme of the peroxisomal beta-oxidation system, exhibit extensive microvesicular steatohepatitis, leading to hepatocellular regeneration and massive peroxisome proliferation, implying sustained activation of PPARalpha by natural ligands. We now report that mice nullizygous for both PPARalpha and AOX (PPARalpha-/- AOX-/-) failed to exhibit spontaneous peroxisome proliferation and induction of PPARalpha-regulated genes by biological ligands unmetabolized in the absence of AOX. In AOX-/- mice, the hyperactivity of PPARalpha enhances the severity of steatosis by inducing CYP4A family proteins that generate DCAs and since they are not metabolized in the absence of peroxisomal beta-oxidation, they damage mitochondria leading to steatosis. Blunting of microvesicular steatosis, which is restricted to few liver cells in periportal regions in PPARalpha-/- AOX-/- mice, suggests a role for PPARalpha-induced genes, especially members of CYP4A family, in determining the severity of steatosis in livers with defective peroxisomal beta-oxidation. In age-matched PPARalpha-/- mice, a decrease in constitutive mitochondrial beta-oxidation with intact constitutive peroxisomal beta-oxidation system contributes to large droplet fatty change that is restricted to centrilobular hepatocytes. These data define a critical role for both PPARalpha and AOX in hepatic lipid metabolism and in the pathogenesis of specific fatty liver phenotype. (+info)
Altered gene expression pattern in the fatty liver dystrophy mouse reveals impaired insulin-mediated cytoskeleton dynamics.
(12/3223)
The mouse fatty liver dystrophy (fld) mutation is characterized by transient hypertriglyceridemia and fatty liver during the neonatal period, followed by development of a peripheral neuropathy. To uncover the metabolic pathway that is disrupted by the fld mutation, we analyzed the altered pattern of gene expression in the fatty liver of fld neonates by representational difference analysis of cDNA. Differentially expressed genes detected include a novel member of the Ras superfamily of small GTP-binding proteins, a novel Ser/Thr kinase, and several actin cytoskeleton-associated proteins including actin, profilin, alpha-actinin, and myosin light chain. Because these proteins have a potential functional link in the propagation of hormone signals, we investigated cytoskeleton dynamics in fld cells in response to hormone treatment. These studies revealed that preadipocytes from fld mice exhibit impaired formation of actin membrane ruffles in response to insulin treatment. These findings suggest that the altered mRNA expression levels detected in fld tissue represent a compensatory response for the nonfunctional fld gene and that the fld gene product may be required for development of normal insulin response. (+info)
Rapid regression of atherosclerosis induced by liver-directed gene transfer of ApoE in ApoE-deficient mice.
(13/3223)
Apolipoprotein E (apoE) is a multifunctional protein synthesized by the liver and tissue macrophages. ApoE-deficient mice have severe hyperlipidemia and develop accelerated atherosclerosis on a chow diet. Both liver-derived and macrophage-derived apoEs have been shown to reduce plasma lipoprotein levels and slow the progression of atherosclerosis in apoE-deficient mice, but regression of atherosclerosis has not been demonstrated in this model. We utilized second-generation adenoviruses to achieve hepatic expression of human apoE in chow-fed, apoE-deficient mice with established atherosclerotic lesions of different stages. As expected, hepatic expression of human apoE3 significantly reduced plasma cholesterol levels. Liver-derived apoE also accumulated substantially within preexisting atherosclerotic lesions, indicating that plasma apoE gained access to the arterial intima. Hepatic expression of human apoE3 for 6 weeks resulted in significant quantitative regression of both early fatty streak lesions as well as advanced, complex lesions in both the aortic root and the aortic arch. In addition, hepatic expression of apoE induced substantial morphological changes in lesions, including decreased foam cells and increased smooth muscle cells and extracellular matrix content. In parallel, human apoE4 and apoE2 were also expressed in the liver by using recombinant adenoviruses. ApoE4 reduced cholesterol levels to the same extent as did apoE3 and also prevented progression but did not induce significant regression of preexisting lesions. ApoE2 reduced cholesterol levels to a lesser degree than did apoE3 and apoE4 and lesion progression was reduced, but regression was not induced. In summary, (1) regression of preexisting atherosclerotic lesions in apoE-deficient mice can be rapidly induced by hepatic expression of apoE, despite the absence of macrophage-derived apoE; (2) the morphological changes seen in this model of regression resemble those in other animal models, induced over longer periods of time; (3) liver-derived apoE gained access to and was retained by intimal atherosclerotic lesions; and (4) apoE4 was less effective in inducing regression, despite its effects on plasma lipoproteins that were similar to those of apoE3. The rapid regression of preexisiting atherosclerotic lesions induced by apoE gene transfer in apoE-deficient mice could provide a convenient murine model for investigation of the molecular events associated with atherosclerosis regression. (+info)
Do people with similar waist circumference share similar health risks irrespective of height?
(14/3223)
In order to know whether people of similar waist circumference having similar health risks irrespective of height, comparisons of odds ratios for coronary risk factors and fatty liver by echogram were made between the subjects from the first (short, < or = 164.5 cm) and fourth quartiles (tall, > or = 172.4 cm) of height from both the third (84.5 approximately < 89 cm) and fourth (> or = 89 cm) quartiles of waist circumference from 3117 men (ranging 35-64 years old) who underwent routine health examinations in Tokyo. After adjusting for age, and with tall subjects in the same waist circumference category as reference, the odds ratios were significantly higher for the short people from the third quartile of waist circumference for the risk of hypertension (1.62, 95% CI 1.002-2.63), hyperglycemia (3.34, 1.27-9.95) and fatty liver (2.12, 1.30-3.50). However, there were no significant differences in odds ratios of any risk health risks between short people and tall people from the fourth quartile of waist circumference. Although people of prominently large waist circumferences may have similar health risks of the above items irrespective of height, short people have higher health risks than tall people in the moderately large waist circumference population of Japanese men. (+info)
Increased levels of nuclear SREBP-1c associated with fatty livers in two mouse models of diabetes mellitus.
(15/3223)
Hepatic steatosis is common in non-insulin-dependent diabetes and can be associated with fibrosis and cirrhosis in a subset of individuals. Increased rates of fatty acid synthesis have been reported in livers from rodent models of diabetes and may contribute to the development of steatosis. Sterol regulatory element-binding proteins (SREBPs) are a family of regulated transcription factors that stimulate lipid synthesis in liver. In the current studies, we measured the content of SREBPs in livers from two mouse models of diabetes, obese ob/ob mice and transgenic aP2-SREBP-1c436 (aP2-SREBP-1c) mice that overexpress nuclear SREBP-1c only in adipose tissue. The aP2-SREBP-1c mice exhibit a syndrome that resembles congenital generalized lipodystrophy in humans. Both lines of mice develop hyperinsulinemia, hyperglycemia, and hepatic steatosis. Nuclear SREBP-1c protein levels were significantly elevated in livers from ob/ob and aP2-SREBP-1c mice compared with wild-type mice. Increased nuclear SREBP-1c protein was associated with elevated mRNA levels for known SREBP target genes involved in fatty acid biosynthesis, which led to significantly higher rates of hepatic fatty acid synthesis in vivo. These studies suggest that increased levels of nuclear SREBP-1c contribute to the elevated rates of hepatic fatty acid synthesis that leads to steatosis in diabetic mice. (+info)
Sequential production of fatty liver, hepatitis, and cirrhosis in sub-human primates fed ethanol with adequate diets.
(16/3223)
This study reproduces in experimental animals the sequential development of all the liver lesions seen in the human alcoholic: in 15 baboons fed ethanol, all developed fatty liver, five progressed to hepatitis, and five had cirrhosis. Maintenance of a nutritionally adequate regimen despite the intake of inebriating amounts of ethanol (50% of total calories) was achieved by incorporation of the ethanol in a totally liquid diet. Upon ethanol withdrawal, signs of physical dependence, such as seizures and tremors, developed. Ultrastructural changes of the mitochondria and the endoplasmic reticulum were already present at the fatty liver stage and persisted throughout the hepatitis and cirrhosis. The lesions were similar to those observed in alcoholics (including the inflammation and the central sclerosis) and differed from the alterations produced by choline and protein defiencies. At the fatty liver stage, some "adaptive" increases in activity of microsomal enzymes [aniline hydroxylase (EC 1.14.14.1) and the microsomal ethanol oxidizing system] were observed, but these tended to disappear with the development of hepatitis and cirrhosis. Fat accumulation was also much more pronounced in the animals with the hepatitis as compared with those with simple fatty liver (an 18-fold compared with 3- to 4-fold increase in liver triglycerides). The demonstration that these lesions can develop despite an adequate diet indicates that in addition to correction of the nutritional status, control of alcohol intake is mandatory for the management of patients with alcoholic liver injury. (+info)