Increased hepatic CD36 expression with age is associated with enhanced susceptibility to nonalcoholic fatty liver disease

Abstract

CD36 has been associated with obesity and diabetes in human liver diseases, however, its role in age-associated nonalcoholic fatty liver disease (NAFLD) is unknown. Therefore, liver biopsies were collected from individuals with histologically normal livers (n=30), and from patients diagnosed with simple steatosis (NAS; n=26). Patients were divided into two groups according to age and liver biopsy samples were immunostained for CD36. NAFLD parameters were examined in young (12-week) and middle-aged (52-week) C57BL/6J mice, some fed with chow-diet and some fed with low-fat (LFD; 10% kcal fat) or high-fat diet (HFD; 60% kcal fat) for 12-weeks. CD36 expression was positively associated with age in individuals with normal livers but not in NAS patients. However, CD36 was predominantly located at the plasma membrane of hepatocytes in aged NAS patients as compared to young. In chow-fed mice, aging, despite an increase in hepatic CD36 expression, was not associated with the development of NAFLD. However, middle-aged mice did exhibit the development of HFD-induced NAFLD, mediated by an increase of CD36 on the membrane. Enhanced CD36-mediated hepatic fat uptake may contribute to an accelerated progression of NAFLD in mice and humans. Therapies to prevent the increase in CD36 expression and/or CD36 from anchoring at the membrane may prevent the development of NAFLD.

Hepatic Overexpression of CD36 Improves Glycogen Homeostasis and Attenuates High-Fat Diet-Induced Hepatic Steatosis and Insulin Resistance

“…Despite the well-documented function of CD36 in fatty acid uptake (41) and several reports that associate hepatic CD36 signaling with an increased risk of developing liver steatosis (3,5,6,8,42), we showed that overexpression of CD36 in the livers of our transgenic mice did not worsen metabolic functions but rather protected the mice from the detrimental metabolic changes caused by HFD feeding and prolonged fasting. The antisteatotic effect of CD36 is consistent with a report that whole-body CD36 ablation exacerbated hepatic steatosis in the ob/ob background (10) but is contrary to a recent study showing that liver-specific knockout of CD36 reduced the liver lipid content when mice were challenged with HFD (42).…”

“…The hepatic expression of CD36 is under the transcriptional control of the nuclear receptors: liver X receptor (LXR), pregnane X receptor (PXR), peroxisome proliferator-activated receptors (PPARs), and the aryl hydrocarbon receptor (AhR) (4). Some studies have suggested that hepatic CD36, by functioning as a fatty acid transporter, has a role in the pathogenesis of hepatic steatosis (3), obesity (7,8), and age-related hepatic steatosis (5). Furthermore, we and others reported that induction of CD36 was a common factor in fatty liver following the activation of LXR and PXR (6,9).…”

Aging increases the susceptibility of hepatic inflammation, liver fibrosis and aging in response to high-fat diet in mice

“…A recent study reported that increased hepatic CD36 expression with age is associated with enhanced hepatic fat uptake and increased susceptibility to NAFLD (Sheedfar et al 2014). Meanwhile, in another study, HFD-induced obesity primes inflammation in adipose tissue prior to development of hepatic inflammation (van der Heijden et al 2015a).…”

“…Although there has been limited data available regarding the differential effect of HFD feeding on the progression of NAFLD and/or renal injury, a few papers have been published on these topics recently (Sheedfar et al 2014;van der Heijden et al 2015a). A recent study reported that increased hepatic CD36 expression with age is associated with enhanced hepatic fat uptake and increased susceptibility to NAFLD (Sheedfar et al 2014).…”

Genetic ablation of macrohistone H2A1 leads to increased leanness, glucose tolerance and energy expenditure in mice fed a high-fat diet

“…Powdered tissue was homogenized as described previously. 25 Equal amounts of protein were separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, transferred to PVDF membrane (Amersham, Buckinghamshire, UK) and the resulting immune complex was visualized using the Molecular Imager ChemiDoc XRS+System (Bio-Rad, Veenendaal, The Netherlands). Antibodies against phospho-and total AKT were purchased from Cell Signaling (Leiden, The Netherlands).…”