Hepatic fatty acid translocase CD36 upregulation is associated with insulin resistance, hyperinsulinaemia and increased steatosis in non-alcoholic steatohepatitis and chronic hepatitis C

Miquilena-Colina, María E.; Lima-Cabello, Elena; Sánchez-Campos, Sonia; García‐Mediavilla, María Victoria; Fernandez–Bermejo, Miguel; Lozano-Rodríguez, Tamara; Vargas-Castrillón, Javier; Buqué, Xabier; Ochoa, Begoña; Aspichueta, Patricia; González‐Gallego, Javier; García‐Monzón, Carmelo

doi:10.1136/gut.2010.222844

Cited by 363 publications

(277 citation statements)

References 47 publications

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“…31,37 Recently, it was reported that abnormal upregulation of CD36 on the plasma membrane of hepatocytes contributes to hepatic fat accumulation, insulin resistance, and hyper-insulinemia in patients with NAFLD. 38,39 Consistent with these reports, the hepatic mRNA and protein levels of PPAR-g and CD36 were abnormally elevated, and hyperglycemia and hyperinsulinemia were also observed in HFD-fed mice (Figures 6a-c and Table 3), confirming that the PPAR-g-signaling pathway and CD36 are involved in HFD-induced NAFLD. Our data also clearly showed high levels of CYP2E1 mRNA expression and lipid peroxidation products in the livers of HFD-fed mice (Figures 3a and b).…”

Section: Discussionsupporting

confidence: 75%

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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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Section: Discussionsupporting

confidence: 75%

“…CD36 has also been reported to contribute to insulin resistance and hyper-insulinemia. 38,48 Interestingly, the increased level of plasma insulin in the HFD þ oxLDL group under hyperglycemic condition was significantly lower than that of the HFD-fed group (Table 4). Similar results were also obtained with RD þ oxLDL 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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“…In the hyperinsulinaemic, insulin-resistant state, as seen in NAFLD, this tight homeostatic control of lipid and carbohydrate is partially lost. IR is associated with uncontrolled adipose tissue lipolysis as well as increased hepatic expression of fatty acid transporter proteins required for fatty acid uptake into the liver (122). Furthermore, obesity and IR are associated with increased re-esterification of fatty acids (123).…”

Section: Insulinmentioning

confidence: 99%

Mechanisms in endocrinology: Non-alcoholic fatty liver disease in common endocrine disorders

Hazlehurst

Tomlinson

2013

European Journal of Endocrinology

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Non-alcoholic fatty liver disease (NAFLD) is a spectrum of disease spanning from simple benign steatosis to steatohepatitis with fibrosis and scarring that can eventually lead to cirrhosis. Its prevalence is rising rapidly and is developing into the leading indication for liver transplantation worldwide. Abnormalities in endocrine axes have been associated with NALFD, including hypogonadism, hypothyroidism, GH deficiency and hypercortisolaemia. In some instances, correction of the endocrine defects has been shown to have a beneficial impact. While in patients with type 2 diabetes the association with NAFLD is well established and recognised, there is a more limited appreciation of the condition among common endocrine diseases presenting with hormonal excess or deficiency. In this review, we examine the published data that have suggested a mechanistic link between endocrine abnormalities and NAFLD and summarise the clinical data endorsing these observations.

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“…The combination of increased fatty acid release from adipose tissue and decreased clearance by skeletal muscle results in hyperlipidemia and increased reliance on the liver to clear fatty acids (Lewis et al 2002, Jonkers et al 2013, Janssens et al 2015. Hepatic expression of Cd36, a fatty acid transporter, is increased with alcohol or high-fat feeding in mice and in NAFLD (Miquilena-Colina et al 2011, Clugston et al 2014. Hyperinsulinemia alone can stimulate hepatic Cd36 expression, and is suggested as a primary mechanism driving hepatic lipid accumulation (Steneberg et al 2015).…”

Section: Adipose Tissue Lipolysis and Hepatic Lipid Uptakementioning

confidence: 99%

Hepatic lipid accumulation: cause and consequence of dysregulated glucoregulatory hormones

Geisler

Renquist

2017

Journal of Endocrinology

153

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Fatty liver can be diet, endocrine, drug, virus or genetically induced. Independent of cause, hepatic lipid accumulation promotes systemic metabolic dysfunction. By acting as peroxisome proliferator-activated receptor (PPAR) ligands, hepatic non-esterified fatty acids upregulate expression of gluconeogenic, beta-oxidative, lipogenic and ketogenic genes, promoting hyperglycemia, hyperlipidemia and ketosis. The typical hormonal environment in fatty liver disease consists of hyperinsulinemia, hyperglucagonemia, hypercortisolemia, growth hormone deficiency and elevated sympathetic tone. These endocrine and metabolic changes further encourage hepatic steatosis by regulating adipose tissue lipolysis, liver lipid uptake, de novo lipogenesis (DNL), beta-oxidation, ketogenesis and lipid export. Hepatic lipid accumulation may be induced by 4 separate mechanisms: (1) increased hepatic uptake of circulating fatty acids, (2) increased hepatic de novo fatty acid synthesis, (3) decreased hepatic beta-oxidation and (4) decreased hepatic lipid export. This review will discuss the hormonal regulation of each mechanism comparing multiple physiological models of hepatic lipid accumulation. Nonalcoholic fatty liver disease (NAFLD) is typified by increased hepatic lipid uptake, synthesis, oxidation and export. Chronic hepatic lipid signaling through PPARgamma results in gene expression changes that allow concurrent activity of DNL and beta-oxidation. The importance of hepatic steatosis in driving systemic metabolic dysfunction is highlighted by the common endocrine and metabolic disturbances across many conditions that result in fatty liver. Understanding the mechanisms underlying the metabolic dysfunction that develops as a consequence of hepatic lipid accumulation is critical to identifying points of intervention in this increasingly prevalent disease state.

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Hepatic fatty acid translocase CD36 upregulation is associated with insulin resistance, hyperinsulinaemia and increased steatosis in non-alcoholic steatohepatitis and chronic hepatitis C

Cited by 363 publications

References 47 publications

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

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

Mechanisms in endocrinology: Non-alcoholic fatty liver disease in common endocrine disorders

Hepatic lipid accumulation: cause and consequence of dysregulated glucoregulatory hormones

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