Increased Hepatic CD36 Expression Contributes to Dyslipidemia Associated With Diet-Induced Obesity

Abstract

OBJECTIVE-The etiology of type 2 diabetes often involves diet-induced obesity (DIO), which is associated with elevated plasma fatty acids and lipoprotein associated triglycerides. Since aberrant hepatic fatty acid uptake may contribute to this, we investigated whether increased expression of a fatty acid transport protein (CD36) in the liver during DIO contributes to the dyslipidemia that precedes development of type 2 diabetes.RESEARCH DESIGN AND METHODS-We determined the effect DIO has on hepatic CD36 protein expression and the functional consequence of this in terms of hepatic triglyceride storage and secretion. In addition, in vivo adenoviral gene delivery of CD36 to the livers of lean mice was performed to determine if increased hepatic CD36 protein was sufficient to alter hepatic fatty acid uptake and triglyceride storage and secretion.RESULTS-During DIO, CD36 protein levels in the liver are significantly elevated, and these elevated levels correlate with increased hepatic triglyceride storage and secretion. These alterations in liver lipid storage and secretion were also observed upon forced expression of hepatic CD36 in the absence of DIO and were accompanied with a marked rise in hepatic fatty acid uptake in vivo, demonstrating that increased CD36 expression is sufficient to recapitulate the aberrant liver lipid handling observed in DIO.CONCLUSIONS-Increased expression of hepatic CD36 protein in response to DIO is sufficient to exacerbate hepatic triglyceride storage and secretion. As these CD36-mediated effects contribute to the dyslipidemia that often precedes the development of type 2 diabetes, increased hepatic CD36 expression likely plays a causative role in the pathogenesis of type 2 diabetes.

Clinico-Pathological Profile of NAFLD in Type 2 Diabetes Mellitus

“…Similar statistically significant association was also seen in our study group, with Hypertension and dyslipidemia seen in 83.30% of diabetic NASH individuals, and all having elevated levels of triglyceride and low HDL levels [37,38] . Regarding glycemic control, we established that 66.7 % of our study group had uncontrolled diabetes and a significant relationship were made among the diabetic NASH.…”

CD36-deficient congenic strains show improved glucose tolerance and distinct shifts in metabolic and transcriptomic profiles

“…On the other hand, their triglyceride and free fatty acid levels were increased in contrast to the decrease or no change observed in our study (Table 5). Absence of Cd36 also protects mice from insulin resistance associated with high fat diet-induced obesity and hyperlipidemia (Kennedy et al, 2011) and, conversely, increased expression of hepatic Cd36 in response to high fat diet-induced obesity was found to be sufficient to exacerbate hepatic triglyceride storage and secretion (Koonen et al, 2007). One of the mechanisms responsible may lie in the fact that human islets express Cd36 in the plasma membrane as well as in the insulinsecretory granules, and Cd36 activity was deemed important for uptake of fatty acids into b-cells as well as for mediating their modulatory effects on insulin secretion (Noushmehr et al, 2005) .…”

“…One of the mechanisms responsible may lie in the fact that human islets express Cd36 in the plasma membrane as well as in the insulinsecretory granules, and Cd36 activity was deemed important for uptake of fatty acids into b-cells as well as for mediating their modulatory effects on insulin secretion (Noushmehr et al, 2005) . Altogether, it is apparent that the eventual metabolic effect of Cd36 deficiency is tightly linked to a particular setting of both genomic background (for example, PD.SHR4 vs BN.SHR4 (Seda et al, 2002(Seda et al, , 2003b; Table 5 and Supplementary Figure 3) and environmental factors, particularly diet (Febbraio et al, 1999;Hajri et al, 2002;Koonen et al, 2007;Kennedy et al, 2011) or medication (Qi et al, 2002;Seda et al, 2003a;Seda et al, 2008;Krupkova et al, 2010). Therefore, the apparently controversial issue of causal relation between level of Cd36 expression and metabolic outcome may be resolved by adoption of broader conceptual framework incorporating other (eco)genomic factors.…”

Antioxidant Effects of Statins in the Management of Cardiometabolic Disorders

“…TriglyceridesderivedfromcirculatingFFAsaccumulate in the liver, which may lead to the onset of inflammation mediated by CD36. CD36 and its receptor play an important role in facilitating fatty aciduptake,whichprecedesthesecretionandstorage of triglycerides 80,81) . CD36 is also involved in the inflammatoryresponseinbothadipocytesandmacrophages associated with complications of diet-induced obesity 82) .…”