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Fatty acid transport protein (FATP)4 was thought to mediate intestinal lipid absorption, which was disputed by a study using keratinocyte-Fatp4-rescued Fatp4-/- mice. These knockouts when fed with a Western diet showed elevated intestinal triglyceride (TG) and fatty acid levels. To investigate a possible role of FATP4 on intestinal lipid processing, ent-Fatp4 (KO) mice were generated by Villin-Cre-specific inactivation of the Fatp4 gene. We aimed to measure circulating and intestinal lipids in control and KO mice after acute or chronic fat intake or during aging. Remarkably, ent-Fatp4 mice displayed an approximately 30% decrease in ileal behenic, lignoceric, and nervonic acids, ceramides containing these FA, as well as, ileal sphingomyelin, phosphatidylcholine, and phosphatidylinositol levels. Such decreases were concomitant with an increase in jejunal cholesterol ester. After a 2-wk recovery from high lipid overload by tyloxapol and oral-lipid treatment, ent-Fatp4 mice showed an increase in plasma TG and chylomicrons. Upon overnight fasting followed by an oral fat meal, ent-Fatp4 mice showed an increase in plasma TG-rich lipoproteins and the particle number of chylomicrons and very low-density lipoproteins. During aging or after feeding with a high-fat high-cholesterol (HFHC) diet, ent-Fatp4 mice showed an increase in plasma TG, fatty acids, glycerol, and lipoproteins as well as intestinal lipids. HFHC-fed KO mice displayed an increase in body weight, the number of lipid droplets with larger sizes in the ileum, concomitant with a decrease in ileal ceramides and phosphatidylcholine. Thus, enterocyte FATP4 deficiency led to a metabolic shift from polar to neutral lipids in distal intestine rendering an increase in plasma lipids and lipoproteins.NEW & NOTEWORTHY Enterocyte-specific Fatp4 deficiency in mice increased intestinal lipid absorption with elevation of blood lipids during fasting and aging, as well as after an acute oral fat-loading or chronic HFHC feeding. Lipidomics revealed that knockout mice displayed a shift from very long-chain to long-chain fatty acids, and from polar to neutral lipids, predominantly in the ileum. Thus, FATP4 may have a physiological function in the control of blood lipids via metabolic shifts in distal intestine.

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BACKGROUND: Secondary sarcopenia develops as a result of a bedridden state and illnesses, such as cachexia, liver disease, and diabetes. However, there is a lack of animal models to investigate the underlying mechanisms and potential treatments for secondary sarcopenia. Recently, secondary sarcopenia has been associated with the prognosis of nonalcoholic steatohepatitis. This study aimed to investigate whether stroke-prone spontaneously hypertensive rat 5 (SHRSP5/Dmcr) which developed severe nonalcoholic steatohepatitis by a high-fat and high-cholesterol (HFC; containing 2% cholic acid) diet is a useful model of secondary sarcopenia. METHODS: SHRSP5/Dmcr rats were divided into 6 groups fed with a Stroke-Prone (SP: normal chow) or HFC diets for different periods (4, 12, and 20 weeks), and WKY/Izm rats were divided into 2 groups fed an SP or HFC diet. Body weight, food intake, and muscle force were measured weekly for all rats. After the end of the diet period, skeletal muscle strength evoked by electrical stimulation was recorded, blood was collected, and organ weight was measured. The sera were used for biochemical analysis and the organs were used for histopathological analysis. RESULTS: SHRSP5/Dmcr rats fed an HFC diet developed nonalcoholic steatohepatitis, and their skeletal muscles, especially fast muscles, showed atrophy, indicating that muscle atrophy is aggravated by the progression of nonalcoholic steatohepatitis. In contrast, WKY/Izm rats fed an HFC diet did not exhibit sarcopenia. CONCLUSIONS: This study suggests that SHRSP5/Dmcr rats could be a useful novel model for investigate the mechanism of secondary sarcopenia disorder associated with nonalcoholic steatohepatitis.

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Newborns with FATP4 mutations exhibit ichthyosis prematurity syndrome (IPS), and adult patients show skin hyperkeratosis, allergies, and eosinophilia. We have previously shown that the polarization of macrophages is altered by FATP4 deficiency; however, the role of myeloid FATP4 in the pathogenesis of nonalcoholic steatohepatitis (NASH) is not known. We herein phenotyped myeloid-specific Fatp4-deficient (Fatp4M-/-) mice under chow and high-fat, high-cholesterol (HFHC) diet. Bone-marrow-derived macrophages (BMDMs) from Fatp4M-/- mice showed significant reduction in cellular sphingolipids in males and females, and additionally phospholipids in females. BMDMs and Kupffer cells from Fatp4M-/- mice exhibited increased LPS-dependent activation of proinflammatory cytokines and transcription factors PPARγ, CEBPα, and p-FoxO1. Correspondingly, these mutants under chow diet displayed thrombocytopenia, splenomegaly, and elevated liver enzymes. After HFHC feeding, Fatp4M-/- mice showed increased MCP-1 expression in livers and subcutaneous fat. Plasma MCP-1, IL4, and IL13 levels were elevated in male and female mutants, and female mutants additionally showed elevation of IL5 and IL6. After HFHC feeding, male mutants showed an increase in hepatic steatosis and inflammation, whereas female mutants showed a greater severity in hepatic fibrosis associated with immune cell infiltration. Thus, myeloid-FATP4 deficiency led to steatotic and inflammatory NASH in males and females, respectively. Our work offers some implications for patients with FATP4 mutations and also highlights considerations in the design of sex-targeted therapies for NASH treatment.NEW & NOTEWORTHY FATP4 deficiency in BMDMs and Kupffer cells led to increased proinflammatory response. Fatp4M-/- mice displayed thrombocytopenia, splenomegaly, and elevated liver enzymes. In response to HFHC feeding, male mutants were prone to hepatic steatosis, whereas female mutants showed exaggerated fibrosis. Our study provides insights into a sex-dimorphic susceptibility to NASH by myeloid-FATP4 deficiency.

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The effect of Western diets in the gastrointestinal system is largely mediated by their ability to promote alterations in the immunity and physiology of the intestinal epithelium, and to affect the composition of the commensal microbiota. To investigate the response of the colonic epithelium to high-fat/high-cholesterol diets (HFHCDs), we evaluated the synthesis of host defense factors involved in the maintenance of the colonic homeostasis. C57BL/6 mice were fed an HFHCD for 3 weeks and their colons were evaluated for histopathology, gene expression, and microbiota composition. In addition, intestinal permeability and susceptibility to Citrobacter rodentium were also studied. HFHCD caused colonic hyperplasia, loss of goblet cells, thinning of the mucus layer, moderate changes in the composition of the intestinal microbiota, and an increase in intestinal permeability. Gene expression analyses revealed significant drops in the transcript levels of Muc1, Muc2, Agr2, Atoh1, Spdef, Ang4, Camp, Tff3, Dmbt1, Fcgbp, Saa3, and Retnlb. The goblet cell granules of HFHCD-fed mice were devoid of Relmß and Tff3, indicating defective production of those two factors critical for intestinal epithelial defense and homeostasis. In correspondence with these defects, colonic bacteria were in close contact with, and invading the epithelium. Fecal shedding of C. rodentium showed an increased bacterial burden in HFHCD-fed animals accompanied by increased epithelial damage. Collectively, our results show that HFHCD perturbs the synthesis of colonic host defense factors, which associate with alterations in the commensal microbiota, the integrity of the intestinal barrier, and the host's susceptibility to enteric infections.

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AIM: Non-alcoholic steatohepatitis (NASH) increases cardiovascular risk regardless of risk factors in metabolic syndrome. However, the intermediary factors between NASH and vascular disease are still unknown because a suitable animal model has never been established. The stroke-prone (SP) spontaneously hypertensive rat, SHRSP5/Dmcr, simultaneously develops hypertension, acute arterial lipid deposits in mesenteric arteries, and NASH when feed with a high-fat and high-cholesterol (HFC) diet. We investigated whether SHRSP5/Dmcr affected with NASH aggravates the cardiac or vascular dysfunction. METHOD: Wister Kyoto and SHRSP5/Dmcr rats were divided into 4 groups of 5 rats each, and fed with a SP or HFC diet. After 8 weeks of HFC or SP diet feeding, glucose and insulin resistance, echocardiography, blood biochemistry, histopathological staining, and endothelial function in aorta were evaluated. RESULTS: We demonstrate that SHRSP5/Dmcr rats fed with a HFC diet presented with cardiac and vascular dysfunction caused by cardiac fibrosis, endothelial dysfunction, and left ventricular diastolic dysfunction, in association with NASH and hypertension. These cardiac and vascular dysfunctions were aggravated and not associated with the presence of hypertension, glucose metabolism disorder, and/or obesity. CONCLUSIONS: SHRSP5/Dmcr rats may be a suitable animal model for elucidating the organ interaction between NASH and cardiac or vascular dysfunction.

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OBJECTIVE: To compare the effects of high-monounsaturated (MUFA) and polyunsaturated fatty acids (PUFA) against the metabolic disorders elicited by a high-cholesterol diet (HC) in rats. METHODS: Using in vivo dietary manipulation, rats were fed with different diets containing 4% soybean oil (cholesterol free diet) and 1% HC containing 12% olive oil (HC + OO) enriched with MUFA and 12% sunflower oil (HC + SO) enriched with PUFA for 60 d. Serum lipid levels and hepatic steatosis were evaluated after the treatment period. RESULTS: Comparatively, rats treated with HC + OO diet experienced a decrease in the serum LDL-C, VLDL-C and CT levels compared to those fed with HC + SO diet (P < 0.05). Otherwise, HC + OO provoked significant microvesicular steatosis situated in the hepatic acinar zone 1. CONCLUSIONS: HC + OO diet has high absorption velocity in the acinar zone 1 of liver compared to the HC + SO diet. Based on this, the reduction of the LDL-C, VLDL-C and CT serum levels in the animals treated with HC + OO diet may have been caused by the delay in the FA release to the blood.

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Cholesterol homeostasis relies on an intricate network of cellular processes whose deregulation in response to Western type high-fat/cholesterol diets can lead to several life-threatening pathologies. Significant advances have been made in resolving the molecular identity and regulatory function of transcription factors sensitive to fat, cholesterol, or bile acids, but whether body senses the presence of both fat and cholesterol simultaneously is not known. Assessing the impact of a high-fat/cholesterol load, rather than an individual component alone, on cholesterol homeostasis is more physiologically relevant because Western diets deliver both fat and cholesterol at the same time. Moreover, dietary fat and dietary cholesterol are reported to act synergistically to impair liver cholesterol homeostasis. A key insight into the role of protein kinase C-ß (PKCß) in hepatic adaptation to high-fat/cholesterol diets was gained recently through the use of knockout mice. The emerging evidence indicates that PKCß is an important regulator of cholesterol homeostasis that ensures normal adaptation to high-fat/cholesterol intake. Consistent with this function, high-fat/cholesterol diets induce PKCß expression and signaling in the intestine and liver, while systemic PKCß deficiency promotes accumulation of cholesterol in the liver and bile. PKCß disruption results in profound dysregulation of hepatic cholesterol and bile homeostasis and imparts sensitivity to cholesterol gallstone formation. The available results support involvement of a two-pronged mechanism by which intestine and liver PKCß signaling converge on liver ERK1/2 to dictate diet-induced cholesterol and bile acid homeostasis. Collectively, PKCß is an integrator of dietary fat/cholesterol signal and mediates changes to cholesterol homeostasis.

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OBJECTIVE@#To compare the effects of high-monounsaturated (MUFA) and polyunsaturated fatty acids (PUFA) against the metabolic disorders elicited by a high-cholesterol diet (HC) in rats.@*METHODS@#Using in vivo dietary manipulation, rats were fed with different diets containing 4% soybean oil (cholesterol free diet) and 1% HC containing 12% olive oil (HC + OO) enriched with MUFA and 12% sunflower oil (HC + SO) enriched with PUFA for 60 d. Serum lipid levels and hepatic steatosis were evaluated after the treatment period.@*RESULTS@#Comparatively, rats treated with HC + OO diet experienced a decrease in the serum LDL-C, VLDL-C and CT levels compared to those fed with HC + SO diet (P < 0.05). Otherwise, HC + OO provoked significant microvesicular steatosis situated in the hepatic acinar zone 1.@*CONCLUSIONS@#HC + OO diet has high absorption velocity in the acinar zone 1 of liver compared to the HC + SO diet. Based on this, the reduction of the LDL-C, VLDL-C and CT serum levels in the animals treated with HC + OO diet may have been caused by the delay in the FA release to the blood.

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Objective To compare the effects of high-monounsaturated (MUFA) and polyunsaturated fatty acids (PUFA) against the metabolic disorders elicited by a high-cholesterol diet (HC) in rats. Methods Using in vivo dietary manipulation, rats were fed with different diets containing 4% soybean oil (cholesterol free diet) and 1% HC containing 12% olive oil (HC + OO) enriched with MUFA and 12% sunflower oil (HC + SO) enriched with PUFA for 60 d. Serum lipid levels and hepatic steatosis were evaluated after the treatment period. Results Comparatively, rats treated with HC + OO diet experienced a decrease in the serum LDL-C, VLDL-C and CT levels compared to those fed with HC + SO diet (P < 0.05). Otherwise, HC + OO provoked significant microvesicular steatosis situated in the hepatic acinar zone 1. Conclusions HC + OO diet has high absorption velocity in the acinar zone 1 of liver compared to the HC + SO diet. Based on this, the reduction of the LDL-C, VLDL-C and CT serum levels in the animals treated with HC + OO diet may have been caused by the delay in the FA release to the blood.