Regulation Of Lipoprotein Lipase Activity Research Articles

Decoding the role of angiopoietin-like protein 4/8 complex–mediated plasmin generation in the regulation of LPL activity

After feeding, adipose tissue lipoprotein lipase (LPL) activity should be maximized, therefore the potent LPL-inhibitory activity of angiopoietin-like protein 4 (ANGPTL4) must be blocked by ANGPTL8 through formation of ANGPTL4/8 complexes. ANGPTL4/8 tightly binds and protects LPL but also partially inhibits its activity. Recently, we demonstrated ANGPTL4/8 also binds tissue plasminogen activator (tPA) and plasminogen to generate plasmin that cleaves ANGPTL4/8 to restore LPL activity. Although fully active LPL in the fat postprandially is desirable, ANGPTL4/8 removal could subject LPL to profound inhibition by ANGPTL3/8 (the most potent circulating LPL inhibitor), inhibition by other LPL inhibitors like ANGPTL4, ANGPTL3, and ApoC3 or interfere with ApoC2-mediated LPL activation. To understand better these potential paradoxes, we examined LPL inhibition by ANGPTL3/8, ANGPTL4, ANGPTL3, and ApoC3 and LPL stimulation by ApoC2 in the presence of ANGPTL4/8 + tPA + plasminogen. Remarkably, ANGPTL3/8-mediated LPL inhibition was almost completely blocked, with the mechanism being cleavage of fibrinogen-like domain–containing ANGPTL3 present in the ANGPTL3/8 complex. The LPL-inhibitory effects of ANGPTL4, ANGPTL3, and ApoC3 were also largely reduced in the presence of ANGPTL4/8 + tPA + plasminogen. In contrast, the ability of ApoC2 to stimulate LPL activity was unaffected by ANGPTL4/8-mediated plasmin generation. Together, these results explain how plasmin generated by increased postprandial ANGPTL4/8 levels in adipose tissue enables maximal LPL activity by preventing ANGPTL3/8, ANGPTL4, ANGPTL3, and ApoC3 from inhibiting LPL, while permitting ApoC2-mediated LPL activation to occur.

Red-Skin Extracts of Lotus Seeds Alleviate High-Fat-Diet Induced Obesity via Regulating Lipoprotein Lipase Activity

In recent years, obesity has become an epidemic and an important public health concern. This study was designed to explore the anti-obesity effects of red-skin extracts (RSE) from lotus seeds on high-fat-diet (HFD)-fed mice. In this study, a total of 55 phenolic compounds from the RSE were tentatively characterized using a UPLC-Q/TOF-MS system, including 9 phenolic acids and derivatives, 40 flavonoids, 2 proanthocyanidin, and 4 coumarins and derivatives. Our data demonstrated that RSE could significantly ameliorate obesity characteristics of HFD-fed mice by regulating tissue specific lipoprotein lipase (LPL) activities. In detailed, the activity and expression of LPL in adipose tissue was inhibited, and the activity and expression of LPL in skeletal muscle tissue was enhanced. Overall, these findings suggested that RSE from the red skin of lotus seeds could serve as a great candidate for a value-added, functional ingredient due to its anti-obesity effects via the regulation of LPL activity.

478-P: GALNT2 Variant Associates with Increased ANGPTL3 Circulation Level and Obesity

Background: Polypeptide N-Acetylgalactosaminyltransferase 2 (GALNT2) gene has been associated with serum lipid levels, insulin resistance, and adipogenesis. One of its variants, rs4846914 has been shown to associate with Triglycerides and HDL levels in global genome-wide association studies. ANGPTL proteins have emerged as important regulators of lipid metabolism through its regulation of lipoprotein lipase activity. In this study we aimed to evaluate the association between GALNT2 variant with plasma level of ANGPTL3, 8 and apolipoproteins in individuals of Arab ethnicity. Methods: GALNT2 rs4846914 variant was genotyped in a cohort of 278 Arab individuals from Kuwait. Plasma levels of ANGPTL3 and 8 were measured by ELISA. Apolipoproteins were measured by Luminex multiplexing assay. Significance of association signals was assessed using Bonferroni-corrected P-values. Results: The GALNT2 rs4846914_G allele was associated with increased ANGPTL3 but not ANGPTL8 plasma levels. It was associated with obesity status with an odds ratio of 1.45 (CI:1.024-2.055) (P-value =0.036) . It also associated with increased levels of ApoC1 (P-values ≤0.006) and lower levels of HDL (P-values ≤0.05) . Levels of HDL were found to be mediated by interactions between genotypes (AG+GG) at rs4846914 and measures of percentage body fat (PBF) , apolipoproteins A1a, C1 and B48. Conclusions: Association between GALNT2 variant and lipid metabolism could be mediated through the increased ANGPTL3 protein level. Disclosure A.T.Thangavel: None. M.Abu-farha: None. P.Hebbar: None. M.G.Qaddoumi: None. F.Almulla: None. J.Abubaker: None.

Association of Maternal DNA Methylation and Offspring Birthweight.

This study aims to evaluate the association of maternal DNA methylation (DNAm) during pregnancy and offspring birthweight. One hundred twenty-two newborn-mother dyads from the Isle of Wight (IOW) cohort were studied to identify differentially methylated cytosine-phosphate-guanine sites (CpGs) in maternal blood associated with offspring birthweight. Peripheral blood samples were drawn from mothers at 22-38weeks of pregnancy for epigenome-wide DNAm assessment using the Illumina Infinium HumanMethylation450K array. Candidate CpGs were identified using a course of 100 repetitions of a training and testing process with robust regressions. CpGs were considered informative if they showed statistical significance in at least 80% of training and testing samples. Linear mixed models adjusting for covariates were applied to further assess the selected CpGs. The Swedish Born Into Life cohort was used to replicate our findings (n = 33). Eight candidate CpGs corresponding to the genes LMF1, KIF9, KLHL18, DAB1, VAX2, CD207, SCT, SCYL2, DEPDC4, NECAP1, and SFRS3 in mothers were identified as statistically significantly associated with their children's birthweight in the IOW cohort and confirmed by linear mixed models after adjusting for covariates. Of these, in the replication cohort, three CpGs (cg01816814, cg23153661, and cg17722033 with p values = 0.06, 0.175, and 0.166, respectively) associated with four genes (LMF1, VAX2, CD207, and NECAP1) were marginally significant. Biological pathway analyses of three of the genes revealed cellular processes such as endocytosis (possibly sustaining an adequate maternal-fetal interface) and metabolic processes such as regulation of lipoprotein lipase activity (involved in providing substrates for the developing fetus). Our results contribute to an epigenetic understanding of maternal involvement in offspring birthweight. Measuring DNAm levels of maternal CpGs may in the future serve as a diagnostic tool recognizing mothers at risk for pregnancies ending with altered birthweights.

Different Expression of Duodenal Genes Related to Insulin Resistance Between Nonobese Women and Those with Severe Obesity.

The study aim was to identify changes in duodenal gene expression associated with the development of insulin resistance according to the BMI of women. Duodenal samples were assessed by microarray in four groups of women, nonobese women and women with severe obesity, with both low and high insulin resistance. There was a group of shared downregulated differentially expressed genes (DEGs) related to tissue homeostasis and antimicrobial humoral response in women with higher insulin resistance both with severe obesity and without obesity. In the exclusive DEGs found in severe obesity, downregulated DEGs related to the regulation of the defense response to bacterium and cell adhesion, involving pathways related to the immune system, inflammation, and xenobiotic metabolism, were observed. In the exclusive DEGs from nonobese women with higher insulin resistance, upregulated DEGs mainly related to the regulation of lipoprotein lipase activity, very low-density lipoprotein particle remodeling, lipid metabolic process, antigen processing, and the presentation of peptide antigen were found. Independent of BMI, higher insulin resistance was associated with a downregulation of duodenal DEGs mainly related to the immune system, inflammation, and xenobiotic metabolism. Also, intestinal lipoprotein metabolism may have a certain relevance in the regulation of insulin resistance in nonobese women.

Regulation of angiopoietin-like protein 8 expression under different nutritional and metabolic status.

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease with increasing prevalence worldwide. Angiopoietin-like protein 8 (ANGPTL8), a member of the angiopoietin-like protein family, is involved in glucose metabolism, lipid metabolism, and energy homeostasis and believed to be associated with T2DM. Expression levels of ANGPTL8 are often significantly altered in metabolic diseases, such as non-alcoholic fatty liver disease (NAFLD) and diabetes mellitus. Studies have shown that ANGPTL8, together with other members of this protein family, such as angiopoietin-like protein 3 (ANGPTL3) and angiopoietin-like protein 4 (ANGPTL4), regulates the activity of lipoprotein lipase (LPL), thereby participating in the regulation of triglyceride related lipoproteins (TRLs). In addition, members of the angiopoietin-like protein family are varyingly expressed among different tissues and respond differently under diverse nutritional and metabolic status. These findings may provide new options for the diagnosis and treatment of diabetes, metabolic syndromes and other diseases. In this review, the interaction between ANGPTL8 and ANGPTL3 or ANGPTL4, and the differential expression of ANGPTL8 responding to different nutritional and metabolic status during the regulation of LPL activity were reviewed.

Lysosomal acid lipase regulates fatty acid channeling in brown adipose tissue to maintain thermogenesis

Lysosomal acid lipase (LAL) is the only known enzyme, which hydrolyzes cholesteryl esters and triacylglycerols in lysosomes of multiple cells and tissues. Here, we explored the role of LAL in brown adipose tissue (BAT). LAL-deficient (Lal−/−) mice exhibit markedly reduced UCP1 expression in BAT, modified BAT morphology with accumulation of lysosomes, and mitochondrial dysfunction, consequently leading to regular hypothermic events in mice kept at room temperature. Cold exposure resulted in reduced lipid uptake into BAT, thereby aggravating dyslipidemia and causing life threatening hypothermia in Lal−/− mice. Linking LAL as a potential regulator of lipoprotein lipase activity, we found Angptl4 mRNA expression upregulated in BAT. Our data demonstrate that LAL is critical for shuttling fatty acids derived from circulating lipoproteins to BAT during cold exposure. We conclude that inhibited lysosomal lipid hydrolysis in BAT leads to impaired thermogenesis in Lal−/− mice.

The comprehensive liver transcriptome of two cattle breeds with different intramuscular fat content

Intramuscular fat (IMF) content is an important determinant factor of meat quality in cattle. There is significant difference in IMF content between Jinnan and Simmental cattle. Here, to identify candidate genes and networks associated with IMF deposition, we deeply explored the transcriptome architecture of liver in these two cattle breeds. We sequenced the liver transcriptome of five Jinnan and three Simmental cattle, yielding about 413.9 million sequencing reads. 124 differentially expressed genes (DEGs) were detected, of which 53 were up-regulated and 71 were down-regulated in Jinnan cattle. 1282 potentially novel genes were also identified. Gene ontology analysis revealed these DEGs (including CYP21A2, PC, ACACB, APOA1, and FADS2) were significantly enriched in lipid biosynthetic process, regulation of cholesterol esterification, reverse cholesterol transport, and regulation of lipoprotein lipase activity. Genes involved in pyruvate metabolism pathway were also significantly overrepresented. Moreover, we identified an interaction network which related to lipid metabolism, which might be contributed to the IMF deposition in cattle. We concluded that the DEGs involved in the regulation of lipid metabolism could play an important role in IMF deposition. Overall, we proposed a new panel of candidate genes and interaction networks that can be associated with IMF deposition and used as biomarkers in cattle breeding.

Host Factors Alter Effects of Angiopoietin-Like Protein 8 on Glucose Homeostasis in Diabetic Mice.

Recovery of functional beta cell mass offers a biological cure for type 1 diabetes. However, beta cell mass is difficult to regain once lost since the proliferation rate of beta cells after youth is very low. Angiopoietin like-protein 8 (ANGPTL8), a peptide that has a role in the regulation of lipoprotein lipase activity, was reported to increase beta cell proliferation in mice in 2013. Subsequent studies of human ANGPTL8 for short term (3 to 8 days) in non-diabetic mice showed little or no increase in beta cell proliferation. Here, we examined the effect of ANGPTL8 on glucose homeostasis in models that have not been examined previously. We expressed mouse ANGPTL8 using adenovirus in 2 mouse models of diabetes (streptozotocin and Non-Obese Diabetic (NOD) mice) over 2 weeks. Also, we tested ANGPTL8 in NOD mice deficient in leukocyte 12-lipoxygenase (12LO), an enzyme that contributes to insulitis and loss of beta cell function in NOD, in an effort to determine whether 12LO deficiency alters the response to ANGPTL8. Adenovirus-mediated expression of ANGPTL8 lowered blood glucose levels in streptozotocin treated mice without an increase in beta cell proliferation or serum insulin concentration. While ANGPTL8 did not reverse hyperglycemia in overtly hyperglycemic NOD mice or alter glucose homeostasis of non-diabetic NOD mice, ANGPTL8 reduced blood glucose levels in 12LOKO NOD mice. However, the lower glucose levels in 12LOKO NOD were not associated with higher serum insulin levels or beta cell proliferation. In summary, while mouse ANGPTL8 does not increase beta cell proliferation in NOD mice or streptozotocin treated mice in agreement with studies in non-diabetic mice, it lowers blood glucose levels in multiple low-dose streptozotocin induced diabetes and 12LO deficiency indicating that host factors influence the impact of ANGPTL8 on glucose homeostasis.

Differential effects of angiopoietin-like 4 in brain and muscle on regulation of lipoprotein lipase activity.

ObjectiveLipoprotein lipase (LPL) is a key regulator of circulating triglyceride rich lipoprotein hydrolysis. In brain LPL regulates appetite and energy expenditure. Angiopoietin-like 4 (Angptl4) is a secreted protein that inhibits LPL activity and, thereby, triglyceride metabolism, but the impact of Angptl4 on central lipid metabolism is unknown.MethodsWe induced type 1 diabetes by streptozotocin (STZ) in whole-body Angptl4 knockout mice (Angptl4-/-) and their wildtype littermates to study the role of Angptl4 in central lipid metabolism.ResultsIn type 1 (streptozotocin, STZ) and type 2 (ob/ob) diabetic mice, there is a ~2-fold increase of Angptl4 in the hypothalamus and skeletal muscle. Intracerebroventricular insulin injection into STZ mice at levels which have no effect on plasma glucose restores Angptl4 expression in hypothalamus. Isolation of cells from the brain reveals that Angptl4 is produced in glia, whereas LPL is present in both glia and neurons. Consistent with the in vivo experiment, in vitro insulin treatment of glial cells causes a 50% reduction of Angptl4 and significantly increases LPL activity with no change in LPL expression. In Angptl4-/- mice, LPL activity in skeletal muscle is increased 3-fold, and this is further increased by STZ-induced diabetes. By contrast, Angptl4-/- mice show no significant difference in LPL activity in hypothalamus or brain independent of diabetic and nutritional status.ConclusionThus, Angptl4 in brain is produced in glia and regulated by insulin. However, in contrast to the periphery, central Angptl4 does not regulate LPL activity, but appears to participate in the metabolic crosstalk between glia and neurons.

Lipoprotein lipase deficiency in chronic kidney disease is accompanied by down-regulation of endothelial GPIHBP1 expression

Chronic renal failure (CRF) is associated with hypertriglyceridemia and impaired clearance of very low density lipoprotein (VLDL) and chylomicrons which are largely due to lipoprotein lipase (LPL) deficiency/dysfunction. After its release from myocytes and adipocytes, LPL binds to the endothelium in the adjacent capillaries where it catalyzes hydrolysis of triglycerides in VLDL and chylomicrons. The novel endothelium-derived molecule, glycosylphosphatidylinositol-anchored binding protein 1 (GPIHBP1), plays a critical role in LPL metabolism and function by anchoring LPL to the endothelium and binding chylomicrons. GPIHBP1-deficient mice and humans exhibit severe hypertriglyceridemia and diminished heparin-releasable LPL, pointing to the critical role of GPIHBP1 in regulation of LPL activity. Given its central role in regulation of LPL activity and triglyceride metabolism, we explored the effect of chronic kidney disease (CKD) on GPIHBP1 expression. Expression of GPIHBP1 and LPL were determined by reverse transcriptase-polymerase chain reaction, Western blot and immunohistochemical analyses in the adipose tissue, skeletal muscle and myocardium of rats 12weeks after 5/6 nephrectomy (CRF) or sham-operation (control). Compared to the controls, the CRF group exhibited severe hypertriglyceridemia, significant reduction of the skeletal muscle, myocardium and adipose tissue LPL mRNA and protein abundance. This was accompanied by parallel reductions of GPIHBP1 mRNA abundance and immunostaining in the tested tissues. LPL deficiency in CKD is associated with and compounded by GPIHBP1 deficiency. Together these abnormalities contribute to impaired clearance of triglyceride-rich lipoproteins, diminished availability of lipid fuel for energy storage in adipocytes and energy production in myocytes and consequent hypertriglyceridemia, cachexia, muscle weakness and atherosclerosis.

Farnesoid X receptor as a therapeutic target for dyslipidemia

The farnesoid X receptor (FXR) is a nuclear hormone receptor that binds bile acids and regulates bile acid physiology. Bile acids are important in the regulation of plasma cholesterol levels both because bile acids are essential for absorption of cholesterol from the diet and also because conversion of cholesterol to bile acids represents the major pathway for cholesterol elimination from the body. Furthermore, bile acids may modulate plasma triglyceride levels via multiple mechanisms, including indirect regulation of lipoprotein lipase activity. Recently, synthetic FXR agonists have been shown to have strikingly potent activity for reduction of plasma lipid levels and near complete inhibition of lesion formation in multiple murine atherosclerosis models. These compounds have now entered clinical trials and may provide an additional therapeutic modality for further reduction of cardiovascular disease.

An in situ perfusion protocol of rat epididymal adipose tissue useful in metabolic studies

Experimental approaches involving the perfusion of tissues and organs offer the advantage of improved physiological relevance over the use of isolated tissues or cells while at the same time being much more controlled and tissue-specific than studies in vivo. Nevertheless, there have been few metabolic studies performed in perfused white adipose tissue, largely because of the difficulty of the surgical technique involved. Although some methods have been described, they are difficult to use as perfusion protocols and their reproducibility is poor. We have modified a rat perfusion method, based on a modification of the Ho and Meng technique, for use with epididymal white adipose tissue (eWAT), and we present it here as a protocol to be reproduced. We also offer surgical solutions for the most common variants of vessel distributions in rats. Using the protocol described here, the perfused adipose tissue is viable and metabolically active, as indicated by the maintenance of tissue ATP levels and adiponectin secretion and by endogenous lipolysis regulation. Moreover, there is a high level of lipoprotein lipase activity in the endothelium of the tissue, which is heparin-releasable. Thus, this method is a useful and reproducible tool that allows the perfusion of eWAT for use in metabolic studies.

Identification of functional prolactin (PRL) receptor gene expression: PRL inhibits lipoprotein lipase activity in human white adipose tissue.

During lactation serum levels of prolactin (PRL) are elevated, and the activity of lipoprotein lipase (LPL) is decreased in the adipose tissue and increased in the mammary gland. However, PRL has been suggested to affect the adipose tissue in an indirect fashion during lactation. In the present study, we demonstrated expression of four PRL receptor (PRLR) mRNA isoforms (L, I, S1(a), and S1(b)) in human sc abdominal adipose tissue and breast adipose tissue using RT-PCR/Southern blot analysis. In addition, L-PRLR [relative molecular mass (M(r)) 90,000] and I-PRLR (M(r) 50,000) protein expression was detected in human sc abdominal adipose tissue and breast adipose tissue using immunoblot analysis. Two additional protein bands with the molecular weight M(r) 40-35,000 were also detected. The direct effect of PRL on the regulation of LPL activity in human abdominal adipose tissue cultured in vitro was investigated. PRL (500 ng/ml) reduced the LPL activity in human adipose tissue to 31 +/- 7.7%, compared with control. GH (100 ng/ml) also reduced the LPL activity, to 45 +/- 8.6%, compared with control. In agreement with previous studies, cortisol increased the LPL activity and GH inhibited cortisol-induced LPL activity. Furthermore, we found that PRL also inhibited the cortisol-induced LPL activity. Taken together, these results demonstrate a direct effect of PRL, via functional PRLRs, in reducing the LPL activity in human adipose tissue, and these results suggest that LPL might also be regulated in this fashion during lactation.

Metabolic Effects of Rexinoids: Tissue-Specific Regulation of Lipoprotein Lipase Activity

Hypertriglyceridemia is a frequent complication accompanying the treatment of patients with either retinoids or rexinoids, [retinoid X receptor (RXR)-selective retinoids]. To investigate the cellular and molecular basis for this observation, we have studied the effects of rexinoids on triglyceride metabolism in both normal and diabetic rodents. Administration of a rexinoid such as LG100268 (LG268) to normal or diabetic rats results in a rapid increase in serum triglyceride levels. LG268 has no effect on hepatic triglyceride production but suppresses post-heparin plasma lipoprotein lipase (LPL) activity suggesting that the hypertriglyceridemia results from diminished peripheral processing of plasma very low density lipoproteins particles. Treatment of diabetic rats with rexinoids suppresses skeletal and cardiac muscle but not adipose tissue LPL activity. This effect is independent of changes in LPL mRNA. In C2C12 myocytes, LG268 suppresses the level of cell surface (i.e., heparin-releasable) LPL activity without altering LPL mRNA. This effect is very rapid (t(1/2) = 2 h) and is blocked by the transcriptional inhibitor actinomycin D. These studies demonstrate that RXR ligands can have dramatic effects on the post-translational processing of LPL and suggest that skeletal muscle may be an important target of rexinoid action. In addition, these data underscore that the metabolic consequences of RXR activation are distinct from either retinoic acid receptor or peroxisome proliferator-activated receptor activation.

Estrogen regulation of adipose tissue lipoprotein lipase—Possible mechanism of body fat distribution

OBJECTIVE: The purpose of this study was to evaluate the regulation of lipoprotein lipase activity, protein mass, and messenger ribonucleic acid by estradiol. STUDY DESIGN: Premenopausal women not taking exogenous sex steroids had transdermal 17β-estradiol and placebo patches placed in the gluteal region during the early follicular phase of the menstrual cycle. Adipose biopsies were performed from beneath the patches. Adipose tissue lipoprotein lipase activity was determined by a radiometric assay, protein mass was determined by enzyme-linked immunosorbent assay, and messenger ribonucleic acid level was determined by Northern analysis. Comparisons between the treated and placebo sides were analyzed by nonparametric statistics. RESULTS: Adipose tissue from beneath the 17β-estradiol patch had significantly decreased lipoprotein lipase activity and extracellular protein mass than did adipose tissue from beneath the placebo patch. There was no difference in lipoprotein lipase messenger ribonucleic acid levels. CONCLUSIONS: Estrogen decreases lipoprotein lipase activity by a posttranscriptional modification of protein levels. A hypothesis of sex steroid regulation of body fat distribution is proposed. (Am J Obstet Gynecol 1998;178:101-7.)

Nutritional regulation of lipoprotein lipase activity and its messenger RNAs in ewe adipose tissue and heart

Nutritional regulation of lipoprotein lipase activity and its messenger RNAs in ewe adipose tissue and heart

Nitric oxide mediates down regulation of lipoprotein lipase activity induced by tumor necrosis factor- α in brown adipocytes

We previously reported that tumor necrosis factor- α (TNF- α)/cachectin suppresses lipoprotein lipase activity and its gene expression in brown adipocytes differentiated in culture. Recent evidence suggests that the effect of TNF- α over various cells is related to the enhanced production of nitric oxide (NO). The present study examined whether the suppressive effect of TNF- α on lipoprotein lipase activity is mediated by production of NO in the brown adipocytes. A reverse transcription-polymerase chain reaction (RT-PCR) assay revealed that TNF- α caused a concentration- and time-dependent expression of inducible NO synthase in brown adipocytes. Increasing concentrations of TNF- α (0.5–50 ng/ml) for 24 h resulted in a concentration-dependent decrease in lipoprotein lipase activity with reciprocal increase in nitrite production in the medium. The suppressive effect of TNF- α on lipoprotein lipase activity was significantly prevented by NO synthase inhibitors, N G-nitro- l-arginine methyl ester ( l-NAME) and aminoguanidine, but not by d-NAME, an inactive isomer. Furthermore, 8-bromoguanosine 3′,5′-cyclic monophosphate, cell permeant cGMP, suppressed lipoprotein lipase activity and 1 H-[1,2,4] oxadiazolo[4,3- a]quinoxalin-1-one, a selective inhibitor for soluble guanylate cyclase, restored the TNF- α-suppressed lipoprotein lipase activity. These results suggest that TNF- α stimulates brown adipocytes to express inducible NO synthase, followed by production of NO, which in turn mediates the suppressive effect of TNF- α on lipoprotein lipase activity. The effect of NO is mediated, at least partly, through production of cGMP.

Regulation of lipoprotein lipase activity by growth hormone in differentiated adipocytes from sheep.

Regulation of lipoprotein lipase activity by growth hormone in differentiated adipocytes from sheep.

Fatty acids regulate the expression of lipoprotein lipase gene and activity in preadipose and adipose cells.

During fasting, a reduction in lipoprotein lipase (LPL) activity has been observed in rat fat pad with no change in enzyme mass, whereas LPL mRNA and synthesis are increased, suggesting that insulin and/or fatty acids (FA) regulate LPL activity post-translationaly [Doolittle, Ben-Zeev, Elovson, Martin and Kirchgessner (1990) J. Biol. Chem. 265, 4570-4577]. To examine the role of FA, either preadipose Ob1771 cells or Ob1771 and 3T3-F442A adipose cells were exposed to long-chain FA and to 2-bromopalmitate, a non-metabolized FA. A rapid (2-8 h) and dose-dependent increase (up to 6-fold) in LPL mRNA occurred, primarily due to increased transcription, which is accompanied by a decrease (down to 4-fold) in LPL cellular activity. Under these conditions, secretion of active LPL was nearly abolished. Removal of FA led to full recovery of LPL activity. LPL gene expression in 3T3-C2 fibroblasts was not affected by FA treatment. However fatty acid-activated receptor transfected-3T3-C2 cells, which show FA responsiveness, had increased LPL gene expression upon FA addition. LPL synthesis and cellular content appeared unaffected by FA treatment, whereas secretion of LPL was inhibited. These results indicate that FA regulate the post-translational processing of LPL. It is proposed that the regulation of LPL activity by FA is important with regard to the fine-tuning of FA entry into adipocytes during fasting/feeding periods.