Rate Of Hepatic Lipogenesis Research Articles

Novel Strategies to Treat Hepatic Steatosis and Steatohepatitis.

Concordant with soaring obesity rates, nonalcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease in the world. The obesity epidemic demands interventions to reverse obesity-associated hepatic steatosis, NAFLD, and nonalcoholic steatohepatitis, and several new pharmacologic approaches have been developed within the past several years. Steatosis develops when energy delivery to the liver, modulated by rates of hepatic lipogenesis, exceeds the capacity of the liver to utilize or export this energy. Therefore, pharmacologic approaches to reverse hepatic steatosis have focused largely, though not exclusively, on (1) reducing substrate availability to the liver, (2) reducing hepatic lipid synthesis, and (3) increasing hepatic mitochondrial fat oxidation (Figure 1). This Perspective will discuss these three classes of emerging pharmacologic therapies against hepatic steatosis, with the ultimate intent to ameliorate NAFLD and/or nonalcoholic steatohepatitis, and the advantages and pitfalls afforded by each strategy to treat these epidemics of obesity-associated liver disease.

Berberine improves glucogenesis and lipid metabolism in nonalcoholic fatty liver disease

BackgroundNonalcoholic fatty liver disease (NAFLD) is considered a critical hepatic manifestation of metabolic syndrome. Berberine (BBR) exerts anti-hyperglycemic and anti-dyslipidemic effects and can also ameliorate NAFLD. Thus, BBR might exert its therapeutic effect on NAFLD by improving glucolipid metabolism. Here, we investigated the aspects and extent to which glucolipid metabolism were affected by BBR in rats with NAFLD.MethodsThree groups of Sprague–Dawley rats were studied: a control group (n = 6) fed a normal chow diet and a NAFLD group (n = 6) and a NAFLD + BBR group (n = 6) fed a high-fat diet. Normal saline and BBR (150 mg/kg body weight/day for 16 weeks) were administered by gavage. All rats were infused with isotope tracers. The rates of glucose appearance (Raglu), gluconeogenesis (GNG) and glycerol appearance (Ragly) were assessed with 2H and 13C tracers, whereas the rates of hepatic lipogenesis and fatty acid β oxidation were measured using the 3H tracer.ResultsWhen the NAFLD model was successfully induced by administering a high-fat diet, body weight, insulin resistance and dyslipidemia were significantly increased. After the BBR treatment, weight loss, decreased lipid profiles and HOMA-IR, and increased ISI were observed. Meanwhile, BBR reduced Raglu, GNG and hepatic lipogenesis, whereas the rate of fatty acid β oxidation in skeletal muscle showed an increasing trend. Ragly showed a decreasing trend. Based on the results of the histological analysis, BBR obviously attenuated the ectopic liver fat accumulation.ConclusionsBBR improved NAFLD by inhibiting glucogenesis and comprehensively regulating lipid metabolism, and its effect on inhibiting hepatic lipogenesis was much stronger. The improvement may be partly mediated by weight loss. Berberine might be a good choice for patients with NAFLD and glucose metabolic disorder. Future clinical trials need to be conducted to confirm these effects.

Adipose Tissue Lipogenesis and Fat Deposition in Leaner Broiler Chickens

Rates of hepatic lipogenesis and secretion of plasma triglyceride-rich lipoproteins in 6- to 7-wk-old broiler chickens were similar to the overall rate of fat deposition in these birds, although ∼20% of [14C]-labeled VLDL was oxidized to CO2 within 8 h. Only 6–7% of VLDL and portomicron triglyceride was taken up by the abdominal fat pad, but this proportion of total triglyceride flux could account for about 80–85% of the total fatty acids accumulating in that depot. The rate of lipogenesis in adipose tissue was much lower than that in the liver, but it could account for much of the remaining fatty acids. Lipogenesis from [14C]acetate in cultured chicken adipocytes was markedly inhibited by adding VLDL as an exogenous source of fatty acids. However, adipose tissue lipogenesis was not increased in vivo by reduction of plasma lipoprotein flux by genetic selection, by the feeding of a high protein diet or by immunological intervention. The results confirm that adipose tissue lipogenesis makes only a small contribution to adipose tissue growth in normal broilers. Its importance does not increase in response to the reductions in hepatic lipogenesis that accompany genetic or nutritional manipulation of body composition.

Dehydroepiandrosterone Feeding and Protein Phosphorylation, Phosphatases, and Lipogenic Enzymes in Mouse Liver

Dehydroepiandrosterone (DHEA) treatment is effective in preventing or delaying the onset of various genetic and induced disorders of mice and rats. Associated with the beneficial therapeutic effects exerted by action of this steroid is the development of hepatomegaly. To determine whether the changes associated with hepatomegaly also involve alterations in activities of tissue enzymes, we evaluated the effects of DHEA (0.45% in food, w/w) on hepatic protein kinases, phosphatases, and lipogenic enzymes in mice of various strains. The rates of fatty acid and cholesterol syntheses also were evaluated. DHEA administration resulted in profound changes in the sodium dodecylsulfate-polyacrylamide gel electrophoresis patterns of endogenous radiophosphorylated proteins obtained by incubation of liver homogenates with (gamma-32P]ATP. These changes were dependent upon the medium used for homogenization. Thus, when homogenates of liver tissue of DHEA-treated mice were prepared in Tris buffer containing sucrose (0.25 M) there was a marked decrease in phosphorylation of the proteins of relative molecular weight approximately 116,000 (Mr approximately 116,000), approximately 82,000, approximately 80,000, approximately 58,000, approximately 56,000, approximately 48,000, approximately 34,000, and approximately 31,000 compared with controls. With liver homogenates of DHEA-treated mice prepared in Tris buffer alone, there was a marked increase in phosphorylation of the proteins of Mr approximately 70,000, approximately 49,000, approximately 34,000, approximately 31,000, and 28,000 compared with controls. Moreover, the specific activity of kinases for endogenous protein acceptors in liver of control mice was higher than that in liver of DHEA-treated animals. The specific activities of casein kinase, cAMP-dependent protein kinase, and cGMP-dependent protein kinase remained unchanged with DHEA treatment, but the specific activity of histone kinase was increased approximately 30%. Long-term administration of DHEA also was associated with increases in the specific activities of liver AMPase and GTPase (approximately two times), but not of other nucleotidases, alkaline phosphatase, acid phosphatase, glucose-6-phosphatase, or phosphotyrosine phosphatase. The activity of hepatic NADP-linked malic enzyme was increased significantly (two to three times) by DHEA treatment of female mice of three different strains, but was unchanged in male C57BL/6 mice. The specific activities of hepatic glucose-6-phosphate dehydrogenase, NADP-linked isocitrate dehydrogenase, and ATP-citrate lyase were not affected significantly by DHEA treatment of mice. The rate of hepatic lipogenesis, determined by incorporation of tritium from 3H2O into fatty acids, was decreased approximately 70% in DHEA-treated mice, while the rate of cholesterol synthesis was increased approximately 44% compared with controls.

Effects of exogenous melatonin on growth and energy metabolism of chickens

Three experiments utilizing male broiler chicks were conducted to evaluate the effects of pinealectomy, light and exogenous melatonin on chick growth and energetic efficiency. Chicks were pinealectomized, sham operated, or left intact. Other groups of chicks were also treated with dietary melatonin. The two lighting schedules employed were a diurnal light/dark cycle (16L:8D) and constant light (24L:0D). The parameters measured were body weight gain; feed consumption and efficiency; energy retention; efficiency of energy utilization for gain; rates of hepatic lipogenesis and jejunal glucose uptake; and plasma concentrations of triiodothyronine (T 3) and thyroxine (T 4). Light treatment and melatonin affected feed intake only slightly. Gain, gain/feed ratio, and energy retention were significantly lower in birds housed under constant light. Melatonin increased gain, gain/feed ratio and energy retention by an average of 19%. The gain response to melatonin was significantly less when birds were housed under constant light; but there was not a significant light x melatonin interaction for either gain/feed ratio or energy retention. Pinealectomized birds grew significantly slower and less efficiently and were little affected by light treatment. However, the response of pinealectomized birds to melatonin was of the same magnitude as either unoperated or sham operated birds. Constant light significantly depressed and melatonin significantly increased liver lipogenesis, jejunal glucose uptake and plasma T 3 and T 4 concentrations.

Early effects of oestrogen treatment on lipogenesis de novo and on biosynthesis of triacylglycerol from fatty acids in male chick liver

1. 1. Early changes (0–44 hr) in liver and plasma lipid levels and in the rate of hepatic lipogenesis were measured in male chicks after a single intramuscular injection of oestradiol-17β. 2. 2. Chick liver slices were employed to measure the rate of lipogenesis de novo using 2H 2O and the rate of triacylglycerol synthesis from [9,10- 3H] palmitate at various times after injection. 3. 3. The results suggest that oestrogen-induced lipogenesis occurs initially by a rapid and coordinated stimulation of the total hepatic capacity for lipogenesis de novo and for triacylglycerol synthesis from fatty acids. 4. 4. The results are discussed in relation to oestrogen-induced changes in hepatic lipogenic enzymes.

Time course of changes in hepatic metabolism in response to sepsis in the rat: impairment of gluconeogenesis and ketogenesis in vitro.

The time course (12, 24 and 48 h) of changes in blood metabolites, and in gluconeogenesis and ketogenesis, in isolated hepatocytes from rats made septic by caecal ligation and puncture was measured. Blood glucose was not significantly different in septic rats, but lactate was increased at 12, 24 and 48 h; pyruvate and alanine were increased at 48 h. The blood ketone body concentrations were decreased at all times studied after induction of sepsis. These changes were accompanied by increased plasma insulin in the septic rats. The rate of hepatic lipogenesis in vivo was increased at 24 and 48 h. There were appreciable increases in the hepatic concentrations of alanine (200%), lactate (200%) and pyruvate (100%) as well as other intermediates in the gluconeogenic pathway. The hepatic concentrations of acetyl-CoA and ketone bodies were decreased. The rate of gluconeogenesis from added lactate, pyruvate, alanine and glutamine was depressed in isolated hepatocytes from septic rats at 24 and 48 h. The basal rate of ketogenesis or the rate from butyrate in isolated hepatocytes was not significantly altered by sepsis, whereas the rate from oleate was decreased at all time points. It is concluded that there is an impairment of the capacity for gluconeogenesis and ketogenesis in livers of septic rats. The latter may be due to decreased entry of long-chain acyl-CoA into the mitochondria for oxidation. The possibility that these changes are in part brought about by the hyperinsulinaemia associated with the sepsis is discussed.

Evidence that the stimulation of lipogenesis in the mammary glands of starved lactating rats re-fed with a chow diet is dependent on continued hepatic gluconeogenesis during the absorptive period. Effects of a gluconeogenic inhibitory, mercaptopicolinic acid, in vivo.

The rapid stimulation of lipogenesis in mammary gland that occurs on re-feeding starved lactating rats with a chow diet was decreased (60%) by injection of mercaptopicolinic acid, an inhibitor of hepatic gluconeogenesis at the phosphoenolpyruvate carboxykinase step. Mercaptopicolinate had no effect on lipogenesis in mammary glands of fed lactating rats. The inhibition of lipogenesis persisted in vitro when acini from mammary glands of re-fed rats treated with mercaptopicolinate were incubated with [1-14C]glucose. Mercaptopicolinate added in vitro had no significant effect on lipogenesis in acini from starved-re-fed lactating rats. Mercaptopicolinate prevented the deposition of glycogen and increased the rate of lipogenesis in livers of starved-re-fed lactating rats, whereas it had no significant effect on livers of fed lactating rats. Administration of intraperitoneal glucose restored the rate of mammary-gland lipogenesis in re-fed rats treated with mercaptopicolinate to the values for re-fed rats. Hepatic glycogen deposition was also restored, and the rate of hepatic lipogenesis was stimulated 5-fold. It is concluded that stimulation of mammary-gland lipogenesis on re-feeding with a chow diet after a period of starvation is in part dependent on continued hepatic gluconeogenesis during the absorptive period. Possible sources of the glucose precursors are discussed.

Efficient hepatic glycogen synthesis in refeeding rats requires continued carbon flow through the gluconeogenic pathway.

Intragastric infusion of [1-14C]glucose into awake, fasted rats at rates that produced physiological increases in the circulating glucose concentration resulted in active glycogen deposition in liver. However, degradation of this glycogen revealed extensive randomization of the label among the carbon atoms of glucose. By contrast, muscle glycogen-glucose was labeled primarily in C-1. Treatment of rats with 3-mercaptopicolinic acid, a potent inhibitor of phosphoenol-pyruvate carboxykinase, prior to [1-14C]glucose infusion reduced hepatic glycogen synthesis by 85%; this glycogen contained most of its label in C-1 of glucose. The additional infusion of unlabeled glycerol, which enters the gluconeogenic pathway distal to the 3-mercaptopicolinic acid block, reinstated hepatic glycogen synthesis, but again the label was associated almost exclusively with C-1. In all animals treated with 3-mercaptopicolinic acid, plasma lactate concentrations rose markedly, as did the rate of hepatic lipogenesis. When [1-14C]glucose was infused into pentobarbital-treated rats or administered to awake animals as a large intragastric bolus, the degree of isotopic randomization in liver glycogen-glucose was considerably reduced when compared with that seen in the awake, infused state. The data support the concept that under normal refeeding conditions the bulk of liver glycogen is formed by an indirect pathway involving the sequence glucose ----lactate----glucose-6-P----glycogen, whereas muscle glycogen is formed by the conventional, direct pathway: glucose----glucose-6-P----glycogen. They also establish that a predominantly direct mechanism can be induced in liver, but only under artificial conditions, e.g. chemical blockade of the gluconeogenic sequence, pentobarbital anesthesia, or the administration of massive glucose loads that lead to severe hyperglycemia.

The adaptive effects of dietary fish and safflower oil on lipid and lipoprotein metabolism in perfused rat liver

To elucidate the mechanisms underlying the plasma triacylglycerol-lowering effects of certain fish oils, livers from male rats fed either a standard commercial diet (controls) or diets supplemented with 15% (w/w) fish or safflower oils were perfused with undiluted rat blood. Rates of hepatic lipogenesis, measured by the incorporation of 3H 2O into fatty acids, followed the order: control > safflower oil > fish oil. Secretion of newly synthesized fatty acids in very-low-density lipoproteins was also inhibited by the feeding of both oil-supplemented diets with the greater suppression being seen in livers from animals fed fish oil. The hepatic release of very-low-density lipoprotein triacylglycerol mass was also significantly depressed in animals fed the fish oil-supplemented diet but not in those fed safflower oil. Ketogenesis did not differ between livers from rats fed the control and safflower oil diets but was significantly raised in the fish oil group. Increased ketogenesis with fish oil was paralleled by a decrease in the sensitivity of carnitine palmitoyl transferase of isolated mitochondria to inhibition by malonyl-CoA. The inhibitory effect of malonyl-CoA in the safflower oil group was intermediate between that in the fish oil and control groups. Activities of glycerophosphate acyltransferase with either palmitoyl-CoA or oleyl-CoA were increased by feeding oil-supplemented diets. Activity with palmitoyl-CoA that was suppressible by N-ethylmaleimide was also considerably diminished in both groups. The results indicate that the lowering of plasma triacylglycerols by fish oil reflects: (a) diminished lipogenesis; (b) increased fatty acid oxidation possibly in peroxisomes; and (c) diminished secretion of triacylglycerols by the liver.

In vivo inhibition of hepatic lipogenesis in the rat by cyclandelate (3, 3′, 5-trimethylcyclohexanylmandelate)

Rates of hepatic lipogenesis were measured in vivo in rats by incorporation into lipids of [ 3H] from injected [ 3H]H 2O 17 hr after a single oral dose of cyclandelate (3, 3′,5-trimethylcyclohexanylmandelate, a vasoactive substance). Cyclandelate administration resulted in a significant inhibition (40–60%) of both sterol and fatty acid synthesis in the livers which was independent of the 3.2-fold diurnal variation in the rates of hepatic sterol and fatty acid synthesis. The inhibition of accumulation of newly synthesized fatty acid in intestine also reached statistical significance. The accumulation of newly synthesized sterol was significantly depressed in serum but did not result in any change in the concentration of serum total cholesterol. These results are interpreted in terms of the inhibitory effect of cyclandelate on hepatic 3-hydroxy-3-methylglutaryl-CoA reductase previously reported by us ( Biochem. Pharmac. 32, 649, 1983).

Circadian phase-dependent prolactin mechanisms in hepatic lipogenesis of a teleost.

In the teleost, Fundulus grandis, injections of prolactin early in the light phase cause an immediate 50% depression in the rate of hepatic lipogenesis ([14C]acetate incorporation); 10 h later, that rate has returned to levels not different from controls. Injections of prolactin late in the light phase cause an even more dramatic immediate depression of lipogenesis (79%) followed by a gradual increase in lipogenic rate which is 2.6 times higher than the control rate after 24 h. The stimulation of lipogenesis by prolactin is blocked by simultaneous treatment with indomethacin, an inhibitor of prostaglandin synthesis. These circadian phase-dependent effects of prolactin on hepatic lipogenesis are discussed with reference to possible mechanisms of action exerted by endogenous prolactin rhythms.

Effect of diabetes and diet on the distribution of tracer doses of chromium in rats.

SummaryThe distribution of 51Cr in tissue fractions of various organs in normal rats has been ascertained. Induced diabetes in rats caused no major alterations in the organ distribution of 51Cr. However, the distribution of 51Cr in liver fractions was altered by induced diabetes or by the feeding of high-fat diets. When the rate of hepatic lipogenesis was normal or elevated, chromium appeared to move from the nuclear to the microsomal fraction of liver.