Regulatable fatty acid transport mechanisms are central to the pathophysiology of obesity, fatty liver, and metabolic syndrome

Berk, Paul D.

doi:10.1002/hep.22632

Cited by 42 publications

(49 citation statements)

References 171 publications

(144 reference statements)

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“…Other proteins have been reported to facilitate the cellular uptake of fatty acids into skeletal muscle: FATP1, CD36, and mAspAT/FABPpm (3,21,66). Remarkably, FATP1 mRNA was downregulated in the FATP4.C 2 C 12 cells (Fig.…”

Section: Resultsmentioning

confidence: 89%

FATP4 contributes as an enzyme to the basal and insulin-mediated fatty acid uptake of C₂C₁₂muscle cells

Digel

Staffer

Ehehalt

et al. 2011

American Journal of Physiology-Endocrinology and Metabolism

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The function of membrane proteins in long-chain fatty acid transport is controversial. The acyl-CoA synthetase fatty acid transport protein-4 (FATP4) has been suggested to facilitate fatty acid uptake indirectly by its enzymatic activity, or directly by transport across the plasma membrane. Here, we investigated the function of FATP4 in basal and insulin mediated fatty acid uptake in C2C12 muscle cells, a model system relevant for fatty acid metabolism. Stable expression of exogenous FATP4 resulted in a twofold higher fatty acyl-CoA synthetase activity, and cellular uptake of oleate was enhanced similarly. Kinetic analysis demonstrated that FATP4 allowed the cells to reach apparent saturation of fatty acid uptake at a twofold higher level compared with control. Short-term treatment with insulin increased fatty acid uptake in line with previous reports. Surprisingly, insulin increased the acyl-CoA synthetase activity of C2C12 cells within minutes. This effect was sensitive to inhibition of insulin signaling by wortmannin. Affinity purified FATP4 prepared from insulin-treated cells showed an enhanced enzyme activity, suggesting it constitutes a novel target of short-term metabolic regulation by insulin. This offers a new mechanistic explanation for the concomitantly observed enhanced fatty acid uptake. FATP4 was colocalized to the endoplasmic reticulum by double immunofluorescence and subcellular fractionation, clearly distinct from the plasma membrane. Importantly, neither differentiation into myotubes nor insulin treatment changed the localization of FATP4. We conclude that FATP4 functions by its intrinsic enzymatic activity. This is in line with the concept that intracellular metabolism plays a significant role in cellular fatty acid uptake.

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Section: Resultsmentioning

confidence: 89%

FATP4 contributes as an enzyme to the basal and insulin-mediated fatty acid uptake of C₂C₁₂muscle cells

Digel

Staffer

Ehehalt

et al. 2011

American Journal of Physiology-Endocrinology and Metabolism

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“…7 The current view from experimental studies on the pathogenesis of NASH is also consistent with the importance of steatosis in the development of NASH. 11,34 Thus, we first established a dietary model for hepatic steatosis by feeding wild-type mice an HFD for 23 weeks (Figures 1a, and 2a and c; Tables 3 and 4). Biochemical analyses verified alterations in lipid metabolism in these mice (Table 4).…”

Section: Discussionmentioning

confidence: 99%

A novel murine model for non-alcoholic steatohepatitis developed by combination of a high-fat diet and oxidized low-density lipoprotein

Yimin

Furumaki

Matsuoka

et al. 2012

Laboratory Investigation

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Non-alcoholic steatohepatitis (NASH) is the hepatic manifestation of metabolic syndrome that is characterized by steatosis, inflammation, and fibrosis, and may progress to cirrhosis and carcinoma. To investigate its pathogenic processes, we established a novel murine model for NASH by combination of a high-fat diet (HFD) and oxidized low-density lipoprotein (oxLDL). Mice that received HFD for 23 weeks showed hepatic steatosis, slight fibrosis, and a high level of lipid peroxidation compared with a regular diet (RD)-fed mice. Hepatic injury and elevated tumor necrosis factor (TNF)-a mRNA expression were also detected in these mice. Moreover, oxLDL administration to HFD-fed mice during weeks 21-23 not only aggravated hepatic steatosis, fibrosis, and lipid metabolism, but also resulted in intense inflammation, including severe hepatic injury and inflammatory cell infiltration, which are the typical histological features of NASH. Inflammation was accompanied by increased gene expression of TNF-a and interleukin (IL)-6. Additionally, the livers of RD-fed animals treated with oxLDL during weeks 21-23 were characterized by foamy macrophages and inflammatory cell infiltration along with an elevated IL-6 mRNA level. These results suggest that an increased oxidative state, including HFD-induced intracellular lipid peroxidation and its extracellular source from oxLDL, is the actual trigger for hepatic inflammation in which liver injury is mediated by TNF-a and inflammatory cell accumulation is dependent on IL-6. HFD and oxLDL also induced insulin resistance in mice; additionally, oxLDL downregulated insulin secretion. In this model, CD36 overexpression was observed in the hepatocytes of HFD-fed mice and those treated with HFD and oxLDL, and in the hepatic macrophages of RD-fed mice immediately after oxLDL treatment. In vitro experiments indicated a rapid and transient elevation of CD36 on macrophage plasma membrane in response to oxLDL. Our findings demonstrate that CD36 expressed on hepatocytes and hepatic macrophages mediates the pathophysiology of NASH.

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“…To avoid lipotoxicity of FA excess within the cells, hepatocytes transform the captured FA into triglycerides (TG), which are released in very-low-density lipoproteins to peripheral tissues (18). FAT/CD36 expression is normally weak in hepatocytes (4,28), but we and others have demonstrated that FAT/CD36 gene expression and protein amount increased concomitantly with hepatic TG content in different models of hepatic steatosis (9,13,24). Further studies showed that FAT/CD36 is a common target of lipogenic genes, the upregulation of which promotes hepatic steatosis in a murine model (44).…”

mentioning

confidence: 99%

High insulin levels are required for FAT/CD36 plasma membrane translocation and enhanced fatty acid uptake in obese Zucker rat hepatocytes

Buqué

Cano

Miquilena-Colina

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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Buqué X, Cano A, Miquilena-Colina ME, García-Monzón C, Ochoa B, Aspichueta P. High insulin levels are required for FAT/CD36 plasma membrane translocation and enhanced fatty acid uptake in obese Zucker rat hepatocytes. Am J Physiol Endocrinol Metab 303: E504-E514, 2012. First published June 12, 2012; doi:10.1152/ajpendo.00653.2011In myocytes and adipocytes, insulin increases fatty acid translocase (FAT)/CD36 translocation to the plasma membrane (PM), enhancing fatty acid (FA) uptake. Evidence links increased hepatic FAT/CD36 protein amount and gene expression with hyperinsulinemia in animal models and patients with fatty liver, but whether insulin regulates FAT/CD36 expression, amount, distribution, and function in hepatocytes is currently unknown. To investigate this, FAT/CD36 protein content in isolated hepatocytes, subfractions of organelles, and density-gradient isolated membrane subfractions was analyzed in obese and lean Zucker rats by Western blotting in liver sections by immunohistochemistry and in hepatocytes by immunocytochemistry. The uptake of oleate and oleate incorporation into lipids were assessed in hepatocytes at short time points (30 -600 s). We found that FAT/CD36 protein amount at the PM was higher in hepatocytes from obese rats than from lean controls. In obese rat hepatocytes, decreased cytoplasmatic content of FAT/CD36 and redistribution from low-to middleto middle-to high-density subfractions of microsomes were found. Hallmarks of obese Zucker rat hepatocytes were increased amount of FAT/CD36 protein at the PM and enhanced FA uptake and incorporation into triglycerides, which were maintained only when exposed to hyperinsulinemic conditions (80 mU/l). In conclusion, high insulin levels are required for FAT/CD36 translocation to the PM in obese rat hepatocytes to enhance FA uptake and triglyceride synthesis. These results suggest that the hyperinsulinemia found in animal models and patients with insulin resistance and fatty liver might contribute to liver fat accumulation by inducing FAT/CD36 functional presence at the PM of hepatocytes. fatty acid translocase; steatosis; hyperinsulinemia; free fatty acid; nonalcoholic fatty liver disease; triglyceride FATTY ACID TRANSLOCASE (FAT)/CD36 has been recognized as the most important protein implicated in fatty acid (FA) uptake by skeletal muscle cells, cardiomyocytes, and adipocytes (36,8,16), being required at the plasma membrane (PM) for its function as FA transporter. In these cell types, FAT/CD36 cellular distribution is regulated by muscle contraction and/or insulin, which induce protein translocation to the PM from an intracellular pool (19,31,39). This particular regulation allows these tissues to respond to acute and chronic metabolic requirements, turning FAT/CD36 into a key regulator of whole body lipid homeostasis (8). In certain disorders characterized by a defective response to insulin action in muscular and adipose tissues, such as obesity and type 2 diabetes, when FAT/CD36 protein is increased at the PM, FA uptake also increases (19...

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Regulatable fatty acid transport mechanisms are central to the pathophysiology of obesity, fatty liver, and metabolic syndrome

Cited by 42 publications

References 171 publications

FATP4 contributes as an enzyme to the basal and insulin-mediated fatty acid uptake of C₂C₁₂muscle cells

FATP4 contributes as an enzyme to the basal and insulin-mediated fatty acid uptake of C₂C₁₂muscle cells

A novel murine model for non-alcoholic steatohepatitis developed by combination of a high-fat diet and oxidized low-density lipoprotein

High insulin levels are required for FAT/CD36 plasma membrane translocation and enhanced fatty acid uptake in obese Zucker rat hepatocytes

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Regulatable fatty acid transport mechanisms are central to the pathophysiology of obesity, fatty liver, and metabolic syndrome

Cited by 42 publications

References 171 publications

FATP4 contributes as an enzyme to the basal and insulin-mediated fatty acid uptake of C2C12muscle cells

FATP4 contributes as an enzyme to the basal and insulin-mediated fatty acid uptake of C2C12muscle cells

A novel murine model for non-alcoholic steatohepatitis developed by combination of a high-fat diet and oxidized low-density lipoprotein

High insulin levels are required for FAT/CD36 plasma membrane translocation and enhanced fatty acid uptake in obese Zucker rat hepatocytes

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FATP4 contributes as an enzyme to the basal and insulin-mediated fatty acid uptake of C₂C₁₂muscle cells

FATP4 contributes as an enzyme to the basal and insulin-mediated fatty acid uptake of C₂C₁₂muscle cells