Insulin- and leptin-regulated fatty acid uptake plays a key causal role in hepatic steatosis in mice with intact leptin signaling but not in<i>ob/ob</i>or<i>db/db</i>mice

Ge, Fengxia; Zhou, Shengli; Hu, Chunguang; Lobdell, Harrison; Berk, Paul D.

doi:10.1152/ajpgi.00434.2009

Cited by 54 publications

(74 citation statements)

References 58 publications

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“…Elevated CD36 expression has been reported in the alcohol-exposed liver (11)(12)(13), which was confi rmed in the present study. We hypothesized that Cd36 Ϫ / Ϫ mice would be resistant to alcohol-induced steatosis and that a correlation exists between the alcohol-induced increase in hepatic Cd36 expression and increased FFA uptake.…”

Section: Discussionsupporting

confidence: 91%

“…While increased hepatic FFA uptake has been proposed to contribute to alcoholic steatosis ( 3,13 ), this notion is largely derived from studies performed in vitro. For example, alcohol has been shown to increase [ 3 H]OA uptake into HepG2 cells ( 24 ), and primary hepatocytes isolated from rodents chronically fed alcohol displayed increased [ 3 H]OA uptake ( 11,25 ). While our in vivo FFA uptake data do not support the notion that this process is a signifi cant contributor to alcoholic steatosis, differences in experimental models complicate the interpretation of these data.…”

Section: Evidence Of Dysregulated Hepatic Lipid and Glucose Metabolismentioning

confidence: 99%

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CD36-deficient mice are resistant to alcohol- and high-carbohydrate-induced hepatic steatosis

Clugston

Yuen

et al. 2014

Journal of Lipid Research

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liver failure ( 2 ). As a fi rst stage in the ALD spectrum, alcoholic steatosis has been extensively studied in humans and animal models to better understand the mechanisms leading to fat accumulation in the alcohol-exposed liver. This research has indicated that alcohol has many effects on hepatic lipid metabolism, including dysregulation of pathways associated with fatty acid (FA) synthesis, uptake, and oxidation, and triglyceride (TG) synthesis and export; however, the mechanisms underpinning these changes and their relative importance are only beginning to be understood ( 3 ).CD36 (also known as fatty acid translocase) is a class B scavenger receptor that is expressed on the cell surface and can recognize multiple ligands, including long-chain fatty acids, oxidized lipids, and lipoproteins ( 4 ). CD36 has multiple cell type-specifi c physiological functions; for example, its expression in microvascular endothelial cells is associated with angiogenesis, and in the apical cells of taste buds, it is associated with the detection of dietary fatty acids ( 4, 5 ). CD36 is also a mediator of free fatty acid (FFA) uptake into tissues, particularly adipose, heart, and skeletal muscle ( 6, 7 ). It is thought that CD36 does not normally play a signifi cant role in hepatic FFA uptake; however, under nonphysiological conditions, CD36 is induced in the liver and may contribute to hepatic steatosis ( 6 ). For example, pharmacologic activation of liver X receptors increases CD36 expression and TG accumulation in the liver ( 8 ), adenoviral-mediated overexpression of hepatic CD36 increases FFA uptake and TG accumulation ( 9 ), and liver tissues obtained from patients with nonalcoholic fatty liver disease also have significantly elevated CD36 expression ( 10 ).Our group and others have observed increased hepatic CD36 expression in alcohol-fed mice at the gene and protein levels ( 11-13 ). Given the role of CD36 in facilitating FFA uptake into tissues and the observation that it is upregulated in the alcohol-exposed liver, we hypothesized that CD36 is Abstract CD36 is a scavenger receptor with multiple ligands and cellular functions, including facilitating cellular uptake of free fatty acids (FFAs). Chronic alcohol consumption increases hepatic CD36 expression, leading to the hypothesis that this promotes uptake of circulating FFAs, which then serve as a substrate for triglyceride (TG) synthesis and the development of alcoholic steatosis. We investigated this hypothesis in alcohol-fed wild-type and Cd36 -defi cient ( Cd36 ؊ / ؊ ) mice using low-fat/high-carbohydrate Lieber-DeCarli liquid diets, positing that Cd36 ؊ / ؊ mice would be resistant to alcoholic steatosis. Our data show that the livers of Cd36 ؊ / ؊ mice are resistant to the lipogenic effect of consuming highcarbohydrate liquid diets. These mice also do not further develop alcoholic steatosis when chronically fed alcohol. Surprisingly, we did not detect an effect of alcohol or CD36 deficiency on hepatic FFA uptake; however, the lower baseline levels of hepatic TG in ...

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Section: Discussionsupporting

confidence: 91%

Section: Evidence Of Dysregulated Hepatic Lipid and Glucose Metabolismentioning

confidence: 99%

CD36-deficient mice are resistant to alcohol- and high-carbohydrate-induced hepatic steatosis

Clugston

Yuen

et al. 2014

Journal of Lipid Research

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“…Microvesicular steatosis has been previously reported under conditions of altered fatty acid metabolism ( 52,53 ). The marked increase in CD36 mRNA in livers of ob/ob compared with WT mice has been described previously ( 10,35 ), a fi nding we confi rmed and extended to protein levels. However, this increase is unlikely to contribute to hepatic steatosis of ob/ob mice since steatosis was not reversed but was rather exacerbated by CD36 deletion.…”

Section: Discussionsupporting

confidence: 85%

“…3H ). Livers of ob/ob mice had 20-fold more CD36 mRNA than WT as was previously reported ( 35 ) ( Fig. 4A ), and this was paralleled by 6-fold higher CD36 protein levels ( Fig.…”

Section: Cd36 Defi Ciency Aggravates Hepatic Lipid Accumulation Insupporting

confidence: 84%

“…Thus, CD36 deletion on the ob/ob background aggravated hepatic steatosis human NAFLD ( 34 ), hepatic steatosis in the ob/ob mouse is obesity-associated, spontaneous, and characterized by enhanced DNL ( 26,27 ). Second, increased fatty acid uptake by hepatocytes was reported not to be a major contributor to the steatosis in this model ( 35 ), in contrast to other experimental models of hepatic steatosis ( 12 ). Homozygous ob/ob mice lacking CD36 ( ob-CD36 Ϫ / Ϫ ) were generated and studied for hepatic TG accumulation and VLDL secretion.…”

Section: Electron Microscopymentioning

confidence: 77%

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CD36 deletion reduces VLDL secretion, modulates liver prostaglandins, and exacerbates hepatic steatosis in ob/ob mice

Nassir

Adewole

Brunt

et al. 2013

Journal of Lipid Research

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This article is available online at http://www.jlr.org novo FA synthesis or de novo lipogenesis (DNL), decreased FA oxidation, and reduced secretion of VLDLs ( 1, 2 ).CD36 is a class B scavenger receptor that plays an important role in several pathways of FA utilization. The protein is expressed in many cell types, including lingual taste bud cells, enterocytes, adipocytes, myocytes, and immune cells. On taste bud cells, CD36 is important for FA recognition and fat perception ( 3, 4 ). In skeletal muscle, heart, and adipose tissue, CD36 facilitates tissue FA uptake and utilization ( 5, 6 ). In the small intestine, it is important for chylomicron secretion ( 7 ) and for FA-induced release of secretin and cholecystokinin ( 8 ). In the liver, CD36 is expressed on endothelial, parenchymal, and Kupffer cells ( 9 ). Basal expression of liver CD36 is low but increases in experimental models of hepatic steatosis, such as genetic obesity and highfat feeding ( 10, 11 ) or following activation of the prosteatotic transcription factors liver X receptor (LXR), pregnane X receptor (PXR), and aryl hydrocarbon receptor (AHR) by xenobiotics, bacteria, or cytokines ( 12 ). Mice fed a highfat diet have increased liver CD36 expression associated with enhanced hepatic FA uptake and TG accumulation, and these are prevented by CD36 deletion ( 11 ). Interestingly, however, the prosteatotic effects of a high-fructose diet, which enhances DNL and TG accumulation in the liver ( 13 ), are exacerbated by CD36 deletion ( 14 ).In humans with nonalcoholic fatty liver disease (NAFLD), hepatic CD36 positively correlates with liver fat content ( 15 ), but its relationship to output of VLDL suggests that its impact on hepatic FA metabolism might not be limited to enhancing FA fl ux and TG accumulation. NAFLD is Abstract Recent findings described the role of CD36-mediated signaling in regulating cellular calcium and the release of various bioactive molecules, including the prostaglandins, neurotransmitters, cholecystokinin, and secretin. Here we document the role of CD36 in the secretion of hepatic VLDL. CD36 deletion resulted in 60% suppression of VLDL output in vivo, and VLDL secretion was reduced in vitro using incubated liver slices. The effect of CD36 deletion was mediated by enhancing formation of hepatic prostaglandins D2, F2, and E2. Treatment of CD36-defi cient slices with inhibitors of cyclooxygenases reversed the reduction in triglyceride secretion. We also examined the effect of CD36 deletion on the obesity-associated spontaneous steatosis of the ob/ob mouse that is driven by enhanced de novo lipogenesis. Homozygous ob/ob mice lacking CD36 ( ob-CD36 ؊ / ؊ ) were generated and studied for hepatic triglyceride accumulation and VLDL secretion. Livers of ob/ob mice were steatotic as expected and had 5-fold more CD36 on Kupffer cells and hepatocytes. CD36 deletion exacerbated the steatosis by impairing hepatic triglyceride and apoB secretion through increasing prostaglandin levels. These fi ndings suggest an unappreciated role of CD36 in reg...

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Gallstone and Gallbladder Disease: Biliary Tract and Cholangiopathies

Ceci

Han

Krutsinger

et al. 2023

Comprehensive Physiology

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Insulin- and leptin-regulated fatty acid uptake plays a key causal role in hepatic steatosis in mice with intact leptin signaling but not inob/obordb/dbmice

Cited by 54 publications

References 58 publications

CD36-deficient mice are resistant to alcohol- and high-carbohydrate-induced hepatic steatosis

CD36-deficient mice are resistant to alcohol- and high-carbohydrate-induced hepatic steatosis

CD36 deletion reduces VLDL secretion, modulates liver prostaglandins, and exacerbates hepatic steatosis in ob/ob mice

Gallstone and Gallbladder Disease: Biliary Tract and Cholangiopathies

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