Hepatic Fatty Acid Desaturation Research Articles

Abstract 13320: APOO Knockout Elevates Plasma Cholesterol Levels Independent of LDLR and Accelerates Atherosclerosis in Mice

Introduction: Apolipoprotein O (APOO), also known as MIC26, was first discovered through a functional genomics study aimed at identifying genes differentially regulated in the heart by obesity. While its physiologic role is incompletely understood, recent studies implicate a critical intracellular role for APOO in regulating lipid metabolism. The overall objective of the present study was to determine whether genetic deletion of APOO in mice would affect cholesterol metabolism and accelerate atherosclerosis. Methods and Results: Hepatic Apoo expression was induced in response to hyperlipidemia but was inhibited after simvastatin treatment. Using a novel APOO global knockout ( Apoo -/- ) model and liver-specific APOO knockout ( Alb Cre Apoo fl/f l ) model, we report here that APOO deletion elevates hepatic and plasma cholesterol levels. Then, we bred Apoo -/- mouse onto both the Ldlr and Apoe KO hyperlipidemic mouse models. Female Apoo -/- Apoe -/- mice and Apoo -/- Ldlr -/- mice in both sexes displayed markedly elevated plasma cholesterol levels and more severe atherosclerotic lesions as compared to their littermate controls, implying the effect of APOO on cholesterol metabolism independent of LDLR and APOE. We demonstrate that APOO reduces cholesterol excretion through bile and feces. In addition, APOO deficiency led to hepatic triglycerides accumulation and decreased phospholipid unsaturation by inhibiting the expression of CYB5R3, which is responsible for hepatic fatty acid desaturation and elongation. Conclusions: These data represent the first in vivo experimental validation of the association of APOO with plasma cholesterol metabolism independent of LDLR. These results demonstrate that APOO deficiency led to the decreased CRB5R3 expression and fatty acid unsaturation, which responsible for the decrease of cholesterol excretion and elevated plasma cholesterol levels.

The gut microbiota promotes hepatic fatty acid desaturation and elongation in mice

Interactions between the gut microbial ecosystem and host lipid homeostasis are highly relevant to host physiology and metabolic diseases. We present a comprehensive multi-omics view of the effect of intestinal microbial colonization on hepatic lipid metabolism, integrating transcriptomic, proteomic, phosphoproteomic, and lipidomic analyses of liver and plasma samples from germfree and specific pathogen-free mice. Microbes induce monounsaturated fatty acid generation by stearoyl-CoA desaturase 1 and polyunsaturated fatty acid elongation by fatty acid elongase 5, leading to significant alterations in glycerophospholipid acyl-chain profiles. A composite classification score calculated from the observed alterations in fatty acid profiles in germfree mice clearly differentiates antibiotic-treated mice from untreated controls with high sensitivity. Mechanistic investigations reveal that acetate originating from gut microbial degradation of dietary fiber serves as precursor for hepatic synthesis of C16 and C18 fatty acids and their related glycerophospholipid species that are also released into the circulation.

Long-term administration of olanzapine induces adiposity and increases hepatic fatty acid desaturation protein in female C57BL/6J mice.

Objective(s):Weight gain and metabolic disturbances such as dyslipidemia, are frequent side effects of second-generation antipsychotics, including olanzapine. This study examined the metabolic effects of chronic olanzapine exposure. In addition, we investigated the hepatic fatty acid effects of olanzapine in female C57BL/6J mice fed a normal diet.Materials and Methods:Female C57BL/6J mice orally received olanzapine or normal saline for 7 weeks. The effects of long-term olanzapine exposure on body weight changes, food efficiency, blood glucose, triglyceride (TG), insulin, and leptin levels were observed. Hepatic TG and abdominal fat mass were investigated, and fat cell morphology was analyzed through histopathological methods. The levels of protein markers of fatty acid regulation in the liver, namely fatty acid synthase (FAS) and stearoyl-CoA desaturase-1 (SCD-1), were measured.Results:Olanzapine treatment increased the food intake of the mice as well as their body weight. Biochemical analyses showed that olanzapine increased blood TG, insulin, leptin, and hepatic TG. The olanzapine group exhibited increased abdominal fat mass and fat cell enlargement in abdominal fat tissue. Western blotting of the mouse liver revealed significantly higher (1.6-fold) levels of SCD-1 in the olanzapine group relative to the control group; by contrast, FAS levels in the two groups did not differ significantly.Conclusion:Enhanced lipogenesis triggered by increased hepatic SCD-1 activity might be a probable peripheral mechanism of olanzapine-induced dyslipidemia. Some adverse metabolic effects of olanzapine may be related to the disturbance of lipid homeostasis in the liver.

Molecular interplay between Δ5/Δ6 desaturases and long-chain fatty acids in the pathogenesis of non-alcoholic steatohepatitis

ObjectiveThe mechanisms underlying non-alcoholic steatohepatitis (NASH) are not completely elucidated. In the current study we integrated gene expression profiling of liver biopsies from NASH patients with translational studies in mouse...

Substituting Fish Oil with Crude Palm Oil in the Diet of Atlantic Salmon (Salmo salar) Affects Muscle Fatty Acid Composition and Hepatic Fatty Acid Metabolism

Supplies of marine fish oils (FO) are limited and continued growth in aquaculture production dictates that substitutes must be found that do not compromise fish health and product quality. In this study the suitability of crude palm oil (PO) as a replacement for FO in diets of Atlantic salmon was investigated. Duplicate groups of Atlantic salmon post-smolts were fed four practical-type diets in which the added lipid was either 100% FO and 0% crude PO (0% PO); 75% FO and 25% PO (25% PO); 50% FO and 50% PO (50% PO); and 100% PO, for 30 wk. There were no effects of diet on growth rate or feed conversion ratio nor were any histopathological lesions found in liver, heart or muscle. Lipid deposition was greatest in fish fed 0% PO and was significantly greater than in fish fed 50% and 100% PO. Fatty acid compositions of muscle total lipid were correlated with dietary PO inclusion such that the concentrations of 16:0, 18:1(n-9), 18:2(n-6), total saturated fatty acids and total monoenoic fatty acids increased linearly with increasing dietary PO. The concentration of eicosapentaenoic acid [20:5(n-3)] was reduced significantly with increasing levels of dietary PO but the concentration of docosahexaenoic acid [22:6(n-3)] was significantly reduced only in fish fed 100% PO, compared with the other three treatments. Similar diet-induced changes were seen in liver total lipid fatty acid compositions. Hepatic fatty acid desaturation and elongation activities were approximately 10-fold greater in fish fed 100% PO than in those fed 0% PO. This study suggests that PO can be used successfully as a substitute for FO in the culture of Atlantic salmon in sea water. However, at levels of PO inclusion above 50% of dietary lipid, significant reductions in muscle 20:5(n-3), 22:6(n-3) and the (n-3):(n-6) PUFA ratio occur, resulting in reduced availability of these essential (n-3) highly unsaturated fatty acids to the consumer.

Replacement of Fish Oil with Rapeseed Oil in Diets of Atlantic Salmon (Salmo salar) Affects Tissue Lipid Compositions and Hepatocyte Fatty Acid Metabolism

Duplicate groups of Atlantic salmon post-smolts were fed five practical-type diets in which the added lipid was 100% fish oil [FO; 0% rapeseed oil (0% RO)], 90% FO + 10% RO (10% RO), 75% FO + 25% RO (25% RO), 50% FO + 50% RO (50% RO) or 100% RO, for a period of 17 wk. There were no effects of diet on growth rate or feed conversion nor were any histopathological lesions found in liver, heart, muscle or kidney. The greatest accumulation of muscle lipid was in fish fed 0% RO, which corresponded to significantly lower muscle protein in this group. The highest lipid levels in liver were found in fish fed 100% RO. Fatty acid compositions of muscle lipid correlated with RO inclusion in that the proportions of 18:1(n-9), 18:2(n-6) and 18:3(n-3) all increased with increasing dietary RO (r = 0.98-1.00, P < 0.013). The concentrations of eicosapentaenoic acid [20:5(n-3)] and docosahexaenoic acid [22:6(n-3)] in muscle lipid were significantly reduced (P < 0.05), along with total saturated fatty acids, with increasing dietary RO. Diet-induced changes in liver fatty acid compositions were broadly similar to those in muscle. Hepatic fatty acid desaturation and elongation activities, measured using [1-(14)C] 18:3(n-3), were increased with increasing dietary RO. Limited supplies of marine fish oils require that substitutes be found if growth in aquaculture is to be maintained such that fish health and product quality are not compromised. Thus, RO can be used successfully as a substitute for fish oil in the culture of Atlantic salmon in sea water although at levels of RO >50% of dietary lipid, substantial reductions occur in muscle 20:5(n-3), 22:6(n-3) and the (n-3)/(n-6) polyunsaturated fatty acid (PUFA) ratio, which will result in reduced availability of the (n-3) highly unsaturated fatty acids that are beneficial for human health.

Relationship between hepatic fatty acid desaturation and lipid secretion in the estrogenized chicken.

Desaturation of fatty acids is thought to facilitate their incorporation into glyceride and their subsequent secretion as lipoproteins. However, in the laying hen, the dramatic increase in hepatic lipogenesis is often paralleled by a liver steatosis that may affect egg production and even result in death. The balance between lipid secretion and storage, in relation to the fatty acid desaturation process, was therefore investigated in young male estrogenized chicken. Estrogen stimulation resulted in a dramatic increase in VLDL concentration (40.4 mg/ml versus 0.158 mg/ml in control) and hepatic lipid content (8.61 g/liver versus 1.47 g/liver in control). In estrogenized chickens, VLDL, total liver, and microsomes contained relatively more monounsaturated and less saturated and polyunsaturated fatty acids, whereas hepatic delta 9 desaturase activity was twofold higher. Moreover, in these birds, the proportion of monoenoic fatty acids was greater in VLDL (55%) than in the liver (50%), which was indicative of their preferential secretion. Therefore, under the influence of estrogen, fatty acid synthesis and desaturation are associated with and increased VLDL secretion, which limits the degree of hepatic accumulation of triglyceride and the risk of subsequent steatosis.

Influence of medium‐chain triglycerides on lipid metabolism in the chick

The effect of corn oil, coconut oil, and medium-chain triglyceride (MCT, a glyceride mixture consisting almost exclusively of fatty acids of 8 and 10 carbons in length) ingestion on lipid metabolism was studied in chicks. In chicks fed cholesterol-free diets, MCT ingestion elevated plasma total lipids and cholesterol and depressed liver total lipids and cholesterol when compared to chicks receiving the corn oil diet. As a consequence of the opposite effects of MCT ingestion on plasma and liver cholesterol and total lipids, the plasma-liver cholesterol pool was not altered. When cholesterol was included in the diets, dietary MCT depressed liver and plasma total lipids and cholesterol as compared with corn oil, consequently also lowered the plasmaliver cholesterol pool.The in vitro cholesterol and fatty acid synthesis from acetate-1-(14)C was higher in liver slices from chicks fed MCT than in those from chicks fed corn oil. The percentage of radioactivity from acetate-1-(14)C incorporated into the carboxyl carbon of fatty acids by liver slices was not altered by MCT feeding, indicating that the increased acetate incorporation represented de novo fatty acid synthesis. The conversion of palmitate-1-(14)C to C(18) acids was increased in liver of chicks fed MCT, implying that fatty acid chain elongating activity was also increased. Studies on the conversion of stearate-2-(14)C to mono- and di-unsaturated C(18) acids showed that hepatic fatty acid desaturation activity was enhanced by MCT feeding. Data are presented on the plasma and liver fatty acid composition of chicks fed MCT-, corn oil-, or coconut oil-supplemented diets.

Influence of medium‐chain triglycerides on lipid metabolism in the rat

Lipid metabolism was studied in rats fed diets containing corn oil, coconut oil, or medium-chain triglyceride (MCT), a glyceride mixture containing fatty acids of 8 and 10 carbons in length. The ingestion of MCT-supplemented, cholesterolfree diets depressed plasma and liver total lipids and cholesterol as compared with corn oil-supplemented diets. In rats fed cholesterol-containing diets, plasma cholesterol levels were not influenced by dietary MCT, but liver cholesterol levels were significantly lower than in animals fed corn oil. In vitro cholesterol synthesis from acetate-1-(14)C was lower in liver slices of rats that consumed MCT than in similar preparations from corn oil-fed rats. Studies of fatty acid carboxyl labeling from acetate-1-(14)C and the conversion of palmitate-1-(14)C to C(18) acids by liver slices showed that chain-lengthening activity is greater in the liver tissue of rats fed MCT than in the liver of animals fed corn oil. The hepatic fatty acid desaturation mechanisms, evaluated by measuring the conversion of stearate-2-(14)C to oleate, was also enhanced by feeding MCT.Adipose tissue of rats fed MCT converts acetate-1-(14)C to fatty acids at a much faster rate than does tissue from animals fed corn oil. Evidence is presented to show that the enhanced incorporation of acetate into fatty acids by the adipose tissue of rats fed MCT represents de novo synthesis of fatty acids and not chain-lengthening activity. Data are also presented on the fatty acid composition of plasma, liver, and adipose tissue lipids of rats fed the different fats under study.