Autotaxin (ATX) is a secreted enzyme that generates the bioactive lipid lysophosphatidic acid (LPA). We generated mice with global inducible post-natal inactivation or adipose-specific loss of the Enpp2 gene encoding ATX. The animals are phenotypically unremarkable and exhibit differences in adipocyte size and adipose tissue expression of inflammatory genes after high fat feeding without gross differences in fat distribution or body mass. Surprisingly, both models of Enpp2- deficiency exhibited marked protection from high fat diet-induced hepatic steatosis. This phenotype was not associated with differences in dietary fat absorption but may be accounted for by differences in hepatic expression of genes involved in de novo synthesis of triglycerides. These findings suggest that pharmacological inhibition of ATX might be protective against hepatic steatosis.

In humans and rodents, risk of metabolic syndrome is sexually dimorphic, with an increased incidence in males. Additionally, the protective role of female gonadal hormones is ostensible, as prevalence of type 2 diabetes mellitus (T2DM) increases after menopause. Here, we investigated the influence of estrogen (E2) on the onset of T2DM in female New Zealand obese (NZO) mice. Diabetes prevalence (defined as blood glucose levels >16.6 mmol/l) of NZO females on high-fat diet (60 kcal% fat) in week 22 was 43%. This was markedly dependent on liver fat content in week 10, as detected by computed tomography. Only mice with a liver fat content >9% in week 10 plus glucose levels >10 mmol/l in week 9 developed hyperglycemia by week 22. In addition, at 11 wk, diacylglycerols were elevated in livers of diabetes-prone mice compared with controls. Hepatic expression profiles obtained from diabetes-prone and -resistant mice at 11 wk revealed increased abundance of two transcripts in diabetes-prone mice: Mogat1, which catalyzes the synthesis of diacylglycerols from monoacylglycerol and fatty acyl-CoA, and the fatty acid transporter Cd36. E2 treatment of diabetes-prone mice for 10 wk prevented any further increase in liver fat content and reduced diacylglycerols and the abundance of Mogat1 and Cd36, leading to a reduction of diabetes prevalence and an improved glucose tolerance compared with untreated mice. Our data indicate that early elevation of hepatic Cd36 and Mogat1 associates with increased production and accumulation of triglycerides and diacylglycerols, presumably resulting in reduced hepatic insulin sensitivity and leading to later onset of T2DM.

Supplementary key words cholesterol • lipoprotein • low density lipoprotein • autotaxin • mass spectrometryLysophosphatidic acids (LPAs) are a class of small receptor active phospholipid signaling molecules that promote the growth, survival, and motility of many cell types. LPA, its receptors and enzymes involved in LPA generation and inactivation are implicated in many pathologies including cardiovascular, pulmonary, and neurological diseases, and cancer (1-3). These observations underscore the importance of identifying the sources and mechanisms regulating the bioavailability and signaling actions of LPA that underlie this association with disease processes. LPA is abundant in plasma where it is primarily generated by hydrolysis of lysophospholipids [notably lysophosphatidylcholine (LPC)] by the secreted phospholipase, autotaxin (ATX) (4, 5), and can be degraded by phospholipases and lipid phosphatases, which may contribute to turnover of circulating LPA pools (3, 4). There is significant inter-individual variability in plasma LPA levels in humans (6). Despite some provocative observations, efforts to associate plasma LPA levels with human disease risk have largely been unsuccessful (7). Plasma LPA is prominently associated with serum albumin (6). Lysophospholipids are present in HDLs and LDLs (8); and LDL, particularly oxidized LDL, contains bioactive LPA (9, 10). This association of LPA with LDL is particularly relevant to the possible role of LPA in cardiovascular disease because of the central role played by LDL in atherosclerosis. However, at present, little is known about the metabolism and function of LDL-associated LPA.Understanding the regulation of LPA metabolism and signaling in cardiovascular disease is important because, in humans, heritable variants of the PLPP3 gene encoding lipid phosphate phosphatase 3 (LPP3), an enzyme that can Abstract Lysophosphatidic acids (LPAs) are bioactive radyl hydrocarbon-substituted derivatives of glycerol 3-phosphate. LPA metabolism and signaling are implicated in heritable risk of coronary artery disease. Genetic and pharmacological inhibition of these processes attenuate experimental atherosclerosis. LPA accumulates in atheromas, which may be a consequence of association with LDLs. The source, regulation, and biological activity of LDL-associated LPA are unknown. We examined the effects of experimental hyperlipidemia on the levels and distribution of circulating LPA in mice. The majority of plasma LPA was associated with albumin in plasma from wild-type mice fed normal chow. LDL-associated LPA was increased in plasma from high-fat Western diet-fed mice that are genetically prone to hyperlipidemia (LDL receptor knockout or activated proprotein convertase subtilisin/kexin type 9-overexpressing C57Bl6). Adipose-specific deficiency of the ENPP2 gene encoding the LPA-generating secreted lysophospholipase D, autotaxin (ATX), attenuated these Western diet-dependent increases in LPA. ATX-dependent increases in LDLassociated LPA were observed in isolated incubated plasma. ...

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Dietary inulin decreases circulating ceramides by suppressing neutral sphingomyelinase expression and activity in mice.

The widely expressed lysophosphatidic acid (LPA) selective receptor 4 (LPAR4) contributes to vascular development in mice and zebrafish. LPAR4 regulates endothelial permeability, lymphocyte migration, and hematopoiesis, which could contribute to atherosclerosis. We investigated the role of LPAR4 in experimental atherosclerosis elicited by adeno-associated virus expressing PCSK9 to lower LDL receptor levels. After 20 weeks on a Western diet, cholesterol levels and lipoprotein distribution were similar in WT male and Lpar4Y/− mice (P = 0.94). The atherosclerotic lesion area in the proximal aorta and arch was ∼25% smaller in Lpar4Y/− mice (P = 0.009), and less atherosclerosis was detected in Lpar4Y/− mice at any given plasma cholesterol. Neutral lipid accumulation in aortic root sections occupied ∼40% less area in Lpar4Y/− mice (P = 0.001), and CD68 expression was ∼25% lower (P = 0.045). No difference in α-smooth muscle actin staining was observed. Bone marrow-derived macrophages isolated from Lpar4Y/− mice displayed significantly increased upregulation of the M2 marker Arg1 in response to LPA compared with WT cells. In aortic root sections from Lpar4Y/− mice, heightened M2 “repair” macrophage marker expression was detected by CD206 staining (P = 0.03). These results suggest that LPAR4 may regulate the recruitment of specific sets of macrophages or their phenotypic switching in a manner that could influence the development of atherosclerosis.

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The results indicate that albinism is common in Mexico, although not as common as in a similar Swedish population. A prevalence of albinism of approximately 0.3% was found in the Mexican population, compared to approximately 1% in the Swedish study group. The number of albinos was much higher in both study groups than to be expected from previous estimates. The difference between the Swedish and the Mexican figures may be explained by the general difference in pigmentation between Sweden and Mexico and thus probably by the subsequent lower number of commonly occurring albino foci in the Mexican heritage. It is emphasised that in investigations of children with SVAS, also in countries with a generally high pigmentation level, electro-physiological examinations are important, to be able to reveal albinism, but also to exclude or verify other conditions in the SVAS group, for example neurometabolic conditions.