Fat Oxidation In Liver Research Articles

204-OR: Inhibition of Hepatic ACC on a High-Fat Diet Results in Hyperglycemia and Hepatomegaly Due to Excess Energy Generation

Liver triglyceride accumulation associated with insulin resistance is partially mediated by elevated de novo lipogenesis (DNL); thus, limiting this pathway is a promising therapeutic strategy for NAFLD. Targeted suppression of acetyl-CoA carboxylase (ACC) activity depletes malonyl-CoA resulting in lower DNL and a simultaneous increase in fat oxidation due to activation of CPT-1. Recently developed ACC1/2 liver specific double KO mice (LDKO) are protected from hepatic steatosis and closely recapitulate pharmacological inhibition of ACC1/2 in humans with NAFLD. However, hepatic ACC inhibition causes surprising elevations in circulating triglyceride and glucose concentrations. LDKO mice had worsened glucose tolerance, which was most consequential during a HFD and especially prominent during fasting. Glucose labeling from 2H2O and [U-13C3] lactate was higher in LDKO hepatocytes, an effect that was dependent on the availability of long chain fatty acids, suggesting that loss of malonyl-CoA and activation of CPT-1 promote gluconeogenesis (GNG). Ketogenesis was increased in LDKO hepatocytes and showed limited response to insulin. Acetyl-CoA was elevated in the fed state, as previously reported, but was normal during fasting when hyperglycemia was most prominent. LDKO mice exhibited massive accumulation of liver citrate and a high fasted hepatic energy charge, which are both known to activate GNG. Hence, despite improved hepatic lipid profile and insulin sensitivity, LDKO liver activates GNG. The resulting hyperinsulinemia partially ameliorates the glycemia phenotype, but may also induce hepatomegaly through canonical signaling pathways and effects on energy status. Thus, activation of fat oxidation in liver lowers lipid accumulation, but has downstream metabolic effects on energetically dependent pathways, such as GNG, that may promote elevated glucose levels in contexts of reduced insulin action, such as fasting and diet induced obesity. Disclosure S. Deja: None. J.A. Fletcher: None. B. Kucejova: None. X. Fu: None. C. Kim: None. J. Browning: None. J.D. Horton: Board Member; Self; Pfizer Inc. Consultant; Self; Gilead Sciences, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc. Stock/Shareholder; Self; Catabasis Pharmaceuticals. Other Relationship; Self; Regeneron Pharmaceuticals, Sanofi. S.C. Burgess: None. Funding National Institutes of Health (R01DK078184, P41EB015908); Robert A. Welch Foundation (I-1804)

Feeding docosahexaenoic acid to pigs reduces blood triglycerides and induces gene expression for fat oxidation

Meadus, W. J., Duff, P., Rolland, D., Aalhus, J. L., Uttaro, B., and Dugan, M. E. R. 2011. Feeding docosahexaenoic acid to pigs reduces triglycerides in blood and induces gene expression for fat oxidation in liver and adipose but not in muscle. Can. J. Anim. Sci. 91: 601–612. The essential fatty acids required in diets of humans are linoleic acid (18:2n-6:LA) and α-linolenic acid (18:3n-3: ALA), and these can be elongated and desaturated to form long-chain omega-6 or omega-3, respectively. Even though not considered essential, consumption of long-chain omega-3 fatty acid is recommended for health benefits, including protection against cardiovascular disease. The omega-3 fatty acid, docosahexanoic acid (DHA), was supplemented in pig diets as a dried biomass of the microalgae Schizochytrium to see if there are unique physiological changes associated with DHA feeding. Pigs were fed a diet with 330 mg (low), 3600 mg (medium) or 9400 mg (high) DHA per day for the last 25 d before slaughter at market weight (∼110 kg). Blood triglycerides (TG) were assayed colormetrically and tissue samples were analyzed for gene expression patterns of RNA by quantitative real-time polymerase chain reaction. Fatty acids were analyzed by gas chromatography. Animal performance appeared to increase with DHA, as shown by a 14% improved feed:gain ratio of 2.74±0.27 (P<0.05). Blood triglycerides were reduced significantly from 0.40±0.23 mM to 0.20±0.09 mM. Pigs accumulated 14 times more DHA in their subcutaneous fat (SQ) (10.67 mg g−1) on the high diet compared with the control diet (0.75 mg g−1). Gene analysis showed that the expression of the fat oxidation biomarkers acyl CoA oxidase 1 (ACOX1), peroxisome proliferator-activated receptors alpha (PPARα) and gamma (PPARγ) were stimulated in the SQ and liver. The delta-6 desaturase (D6D) and elongase (Elov5), which are genes involved in the endogenous synthesis of DHA, were unchanged. Fatty acid synthase (FASN) was stimulated in the liver and muscle of pigs on the high DHA diet. Analysis of gene transcription activity suggested fat metabolism was stimulated in the liver and SQ fat, but the genes involved in the endogenous production of DHA remained unchanged.

Astaxanthin lowers blood pressure and lessens the activity of the renin-angiotensin system in Zucker Fatty Rats

The ability of astaxanthin to favorably influence the renin-angiotensin system (RAS), blood pressure (BP), and metabolic parameters in Zucker Fatty Rats (ZFR) was examined. In separate experiments, 96 ZFR were equally divided into four groups: control, captopril (30 mg/kg), low astaxanthin (5 mg/kg) and high astaxanthin (25 mg/kg). RAS and insulin systems were examined following recovery from heat stress. RAS was lower in test groups; however, there was no evidence of enhanced insulin sensitivity. Test groups decreased SBP (systolic blood pressure) significantly compared to the control. The tests carried out suggested that RAS was involved in the ability of astaxanthin to lower BP. Astaxanthin at high dosage influenced circulating TNF-α and MCP-1 and lessened fat oxidation in liver and kidneys. Thus, astaxanthin may be considered as a good stress reducer with regards to heat stress. Astaxanthin’s effects on RAS indicate it might overcome perturbations associated with increased activity, especially those related to the cardiovascular system.

Cessation of daily wheel running differentially alters fat oxidation capacity in liver, muscle, and adipose tissue

Physical inactivity is associated with the increased risk of developing chronic metabolic diseases. To understand early alterations caused by physical inactivity, we utilize an animal model in which rats are transitioned from daily voluntary wheel running to a sedentary condition. In the hours and days following this transition, adipose tissue mass rapidly increases, due in part to increased lipogenesis. However, whether a concurrent decrease in fatty acid oxidative capacity (FAO) in skeletal muscle, liver, and adipose tissue occurs during this period is unknown. Following 6 wk of access to voluntary running wheels (average distance of approximately 6 km a night), rats were rapidly transitioned to a sedentary state by locking the wheels for 5 h (WL5) or 173 h (WL173). Complete ([(14)C]palmitate oxidation to (14)CO(2)) and incomplete ([(14)C]palmitate oxidation to (14)C-labeled acid soluble metabolites) was determined in isolated mitochondrial and whole homogenate preparations from skeletal muscle and liver and in isolated adipocytes. Strikingly, the elevated complete FAO in the red gastrocnemius at WL5 fell to that of rats that never ran (SED) by WL173. In contrast, hepatic FAO was elevated at WL173 above both WL5 and SED groups, while in isolated adipocytes, FAO remained higher in both running groups (WL5 and WL173) compared with the SED group. The alterations in muscle and liver fat oxidation were associated with changes in carnitine palmitoyl transferase-1 activity and inhibition, but not significant changes in other mitochondrial enzyme activities. In addition, peroxisome proliferator-activated receptor coactivator-1alpha mRNA levels that were higher in both skeletal muscle and liver at WL5 fell to SED levels at WL173. This study is the first to demonstrate that the transition from high to low daily physical activity causes rapid, tissue-specific changes in FAO.