Thyroid hormone controls carnitine status through modifications of γ-butyrobetaine hydroxylase activity and gene expression

The carnitine system plays a key role in β-oxidation of long-chain fatty acids by permitting their transport into the mitochondrial matrix. The effects of hypothyroidism and hyperthyroidism were studied on γ-butyrobetaine hydroxylase (BBH), the enzyme responsible for carnitine biosynthesis in the rat. In rat liver, BBH activity was decreased in the hypothyroid state and increased in hyperthyroid animals. The modifications in BBH activity correlated with changes in the enzyme Vmax values. These changes were shown to be related to hepatic BBH mRNA abundance. Thyroid hormones are known to interact with lipid metabolism, in particular by increasing long-chain fatty acid oxidation through activation of carnitine-dependent fatty acid import into mitochondria. Our study showed that thyroid hormones also increased carnitine bioavailability. Received 23 October 2001; received after revision 11 January 2002; accepted 15 January 2002     

Glucose-evoked recovery of hepatic thyroxine 5'-deiodinase independent of de novo protein synthesis in fasted rat

The glucose-evoked recovery of Type I thyroxine 5'-deiodinase activity in the hepatic microsomes of fasted rat was not inhibited by either cycloheximide, puromycin or actinomycin D during 3 h after glucose feeding; however, [3H]-leucine uptake by the liver or the hepatic microsomal fraction was significantly inhibited by cycloheximide and puromycin but not by actinomycin D. These results indicate that the glucose-evoked recovery of deiodinase activity may be independent of de novo protein synthesis.     

Studying non-alcoholic fatty liver disease with zebrafish: a confluence of optics, genetics, and physiology

Obesity is a public health crisis. New methods for amelioration of its consequences are required because it is very unlikely that the social and economic factors driving it will be reversed. The pathological accumulation of neutral lipids in the liver (hepatic steatosis) is an obesity-related problem whose molecular underpinnings are unknown and whose effective treatment is lacking. Here I review how zebrafish, a powerful model organism long-used for studying vertebrate developmental programs, is being harnessed to uncover new factors that contribute to normal liver lipid handling. Attention is given to dietary models and individual mutants. I speculate on the possible roles of non-hepatocyte residents of the liver, the adipose tissue, and gut microbiome on the development of hepatic steatosis. The highlighted work and future directions may lead to fresh insights into the pathogenesis and treatment of excess liver lipid states.     

Alpha 1-adrenergic stimulation of ketogenesis and fatty acid oxidation is associated with inhibition of lipogenesis in rat hepatocytes

The effect of norepinephrine on fatty acid synthesis (3H2O incorporation into fatty acids), on fatty acid oxidation to CO2 and on ketogenesis was studied in isolated hepatocytes of fed rats. After incubation with norepinephrine (50 microM), lipogenesis was lower (5.7 +/- 1.1 nmoles 3H2O incorporated into fatty acids/mg dry weight/30 min) than in controls (7.5 +/- 1.7; n = 6, p less than 0.02). In contrast, (1-14C) palmitate conversion into total ketone bodies was increased to 10.9 +/- 1.8 nmoles/mg/30 min with norepinephrine, vs 8.5 +/- 1.6 in controls (p less than 0.05), and more (1-14C) palmitate was converted to 14CO2 with norepinephrine than in controls (1.48 +/- 0.10 nmoles/mg/30 min vs 1.06 +/- 0.11, p less than 0.05). The inhibitory effect of norepinephrine on lipogenesis was abolished by addition of the alpha 1-receptor blocker prazosin, but not by alpha 2 or beta-blockers. The results demonstrate that the ketogenic effect of norepinephrine is coupled with an inhibitory effect on lipogenesis which may be explained by diminished activity of acetyl-CoA carboxylase, diminished formation of malonyl-CoA and decreased activity of carnitine palmitoyl transferase I.     

Glucose-evoked recovery of hepatic thyroxine 5′-deiodinase independent of de novo protein synthesis in fasted rat

Summary The glucose-evoked recovery of Type I thyroxine 5-deiodinase activity in the hepatic microsomes of fasted rat was not inhibited by either cycloheximide, puromycin or actinomycin D during 3 h after glucose feeding; however, [³H]-leucine uptake by the liver or the hepatic microsomal fraction was significantly inhibited by cycloheximide and puromycin but not by actinomycin D. These results indicate that the glucose-evoked recovery of deiodinase activity may be independent of de novo protein synthesis.     

Comparison in genetically obese and normal rats of the uptake and incorporation of labelled lauric acid, oleic acid, and glycerol by the isolated perfused liver]

Lauric acid, labelled oleic acid and glycerol are perfused in isolated liver of fafa Rats and Wistar Rats previously subjected to fasting. They synthesize TG and PL de novo, though in long time experiments with the normal Rat, the most important method of synthesis is an exchange of AG of the endogenous glycerolipids. However PL are not synthesized with lauric acid. In the livers of fafa Rats the synthesis of TG with oleic acid and glycerol is higher than in livers of Wistar Rats: 16:0 18 : 1 18: 1, 16:0 18: 1 18: 2, 18 : 1 18 :1 18:1, 16 : 0 16 :0 18 : 1 (this TG is not present in liver of Wistar Rat). The hepatic synthesis of PL by the fafa Rat, is less important after 15 min while it is important with Wistar Rats. The synthesized TG with lauric acid (only the TG 12 : 0 12 : 0 12 : 0 with the fafa Rat) are more rapidly oxidized by liver of obese Rat than by liver of normal Rat.     

Oxygen consumption and biosynthetic function in perfused liver from rats at different stages of development

Changes in mitochondrial function were studied in perfused liver from rats aged 24 – 365 days. Oxygen consumption together with the rates of gluconeogenesis, urea synthesis and ketogenesis were determined. Basal mitochondrial respiration as well as the ability of the liver to synthesize glucose, urea and ketone bodies declined from 24- to 365-day-old rats. On the other hand, on transition from 24 to 60 days the liver oxidation rate of hexanoate, sorbitol and glycerol is enhanced, but not of ketone bodies or palmitate. Our results show that the transition from weaning to middle age is accompanied by defined changes in hepatic substrate oxidation. From the observed time course of the decrease in basal and substrate-stimulated oxygen consumption, it is concluded that in rat liver cells a decline in respiratory chain function, long-chain fatty acid and ketone body metabolism, gluconeogenesis and ureogenesis occurs at a relatively early life stage. Received 19 June 1998; received after revision 11 September 1998; accepted 11 September 1998     

Defect of uric acid uptake in Dalmatian dog liver

Summary The uptake rate of uric acid into liver slices of the Dalmatian dog was found to be significantly lower compared with that in the beagle. Since there was no difference in the hepatic uricase activity between the two breeds, the abnormality of uric acid metabolism in the Dalmatian dog is considered to result from a defective hepatic transport system for uric acid.     

α1-Adrenergic stimulation of ketogenesis and fatty acid oxidation is associated with inhibition of lipogenesis in rat hepatocytes

Summary The effect of norepinephrine on fatty acid synthesis (³H₂O incorporation into fatty acids), on fatty acid oxidation to CO₂ and on ketogenesis was studied in isolated hepatocytes of fed rats. After incubation with norepinephrine (50 M), lipogenesis was lower (5.7±1.1 nmoles³H₂O incorporated into fatty acids/mg dry weight/30 min) than in controls (7.5±1.7; n=6, p<0.02). In contrast, (1-¹⁴C) palmitate conversion into total ketone bodies was increased to 10.9±1.8 nmoles/mg/30 min with norepinephrine, vs 8.5±1.6 in controls (p<0.05), and more (1-¹⁴C) palmitate was converted to¹⁴CO₂ with norepinephrine than in controls (1.48±0.10 nmoles/mg/30 min vs 1.06±0.11, p<0.05). The inhibitory effect of norepinephrine on lipogenesis was abolished by addition of the ₁-receptor blocker prazosin, but not by ₂ or -blockers. The results demonstrate that the ketogenic effect of norepinephrine is coupled with an inhibitory effect on lipogenesis which may be explained by diminished activity of acetyl-CoA carboxylase, diminished formation of malonyl-CoA and decreased activity of carnitine palmitoyl transferase I.     

Tissue-specific induction of intestinal glutathione S-transferases by alpha beta-unsaturated carbonyl compounds

Glutathione S-transferase activity in rat intestinal mucosa was increased by the injection of alpha beta-unsaturated carbonyl compounds such as phorone and diethylmaleate, but that in the liver and kidney was not. Since the administration of cycloheximide completely blocked the increase of the enzyme activity by phorone, the increase of the activity may be due to de novo synthesis rather than enzyme activation.     

In vitro lipid synthesis by lathyrogen-treated L-929 fibroblasts.

Aside from cholesterol, cholesterol esters and lyso-lecithin, the de novo lipid synthesic mechanisms which operate in cells grown in the presence of beta-amino-propionitrile are largely depressed and suggest that there may be in operation specific metabolic control mechanisms for regulation of cellular lipid composition.     

Long-chain fatty acid uptake by skeletal myocytes: a confocal laser scanning microscopy study

Studies of regulation of free fatty acid (FFA) utilization by skeletal muscles have focused on plasma FFA delivery and on intracellular factors affecting FFA metabolism. The present study was conducted to directly analyse the uptake process of fatty acids into single myocytes. Cells were isolated from the rat flexor digitorum brevis muscle. Confocal laser scanning microscopy was utilized to analyse the uptake of the fluorescent fatty acid derivative 12-NBD-stearate, which is not metabolized by muscle tissue. Uptake represented a saturable function of the unbound fatty acid concentration in the medium (K _m 366 ± 118 nM, V _max 2.1 ± 0.3 AU/s) and depended on the medium sodium concentration. Reduced buffer pH increased initial uptake rates, whereas lactate (10 mM) had no effect. Membrane hyper- and depolarization decreased uptake rates. This study demonstrates for the first time kinetic data from isolated myocytes with evidence for a carrier-mediated transport mechanism for long-chain fatty acids. Received 31 March 1998; accepted 8 May 1998     

Periostin in kidney diseases

Chronic kidney disease is an incurable to date pathology, with renal replacement therapy through dialysis or transplantation being the only available option for end-stage patients. A deeper understanding of the molecular mechanisms governing the progression of kidney diseases will permit the identification of unknown mediators and potential novel markers or targets of therapy which promise more efficient diagnostic and therapeutic applications. Over the last years, periostin was established by several studies as a novel key player in the progression of renal disease. Periostin is de novo expressed focally by the injured kidney cells during the development of renal disease. In diverse cohorts of renal disease patients, the expression levels of periostin in the kidney and urine were highly correlated with the stage of the pathology and the decline of renal function. Subsequent studies in animal models demonstrated that periostin is centrally involved in mediating renal inflammation and fibrosis, contributing to the deterioration of renal structure and function. Genetic or pharmaco-genetic inhibition of periostin in animal models of renal disease was efficient in arresting the progression of the pathology. This review will summarize the recent advances on periostin in the field of kidney diseases and will discuss its utility of as a novel target of therapy for chronic kidney disease.     

Effect of taurine administration on liver lipids in guinea pig

The oral administration of 0.4% taurine in drinking water for 14 consecutive days showed the following hepatic effects in male guinea pig. The percentage of tauro-conjugated biliary bile acids was increased from 17.2-54.2%; the ratio liver weight/body weight was increased, and fatty change was induced. Liver triglyceride concentration was accordingly increased; diglyceride and phosphatidylcholine concentrations were reduced by the treatment, while phosphatidylethanolamine level was not affected. These changes suggest an adverse effect of taurine administration on phosphatidylcholine hepatic synthesis.