Cannabinoid 1 receptor in fatty liver

Regnell, Simon E.

doi:10.1111/j.1872-034x.2012.01085.x

Cited by 15 publications

(27 citation statements)

References 87 publications

(139 reference statements)

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“…While present at lower levels than in brain, nevertheless liver expresses the endocannabinoid receptor CB1 (hepatocytes), but only very low level of CB2 (Kuppfer cells) (1,48). Our studies showed that livers of male LKO mice had significantly reduced protein levels of CB1 (Fig.…”

Section: Resultsmentioning

confidence: 99%

FABP1: A Novel Hepatic Endocannabinoid and Cannabinoid Binding Protein

Huang¹,

McIntosh²,

Martin³

et al. 2016

Biochemistry

154

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Endocannabinoids (EC) and cannabinoids are very lipophilic molecules requiring the presence of cytosolic binding proteins that chaperone these molecules to intracellular targets. While three different fatty acid binding proteins (FABP3, 5, 7) serve this function in brain, relatively little is known about how such hydrophobic EC and cannabinoids are transported within the liver. The most prominent hepatic FABP, liver fatty acid binding protein (FABP1, L-FABP), has high affinity for arachidonic acid (ARA) and ARA-CoA—suggesting that FABP1 may also bind ARA-derived ECs (AEA, 2-AG). Indeed, FABP1 bound EC with high affinity as shown by displacement of FABP1-bound fluorescent ligands and by quenching of FABP1 intrinsic tyrosine fluorescence. FABP1 also had high affinity for most non-ARA containing ECs, FABP1 inhibitors, EC uptake/hydrolysis inhibitors, phytocannabinoids, and less so synthetic cannabinoid receptor (CBR) agonists and antagonists. Physiological impact was examined with liver from wild-type (WT) versus FABP1 gene ablated (LKO) male mice. As shown by LC/MS, FABP1 gene ablation significantly increased hepatic levels of AEA, 2-AG, and 2-OG. These increases were not due to increased protein levels of EC synthetic enzymes (NAPEPLD, DAGL) or decreased level of EC degradative enzyme (FAAH), but correlated with complete loss of FABP1, decreased SCP2 (8-fold less prevalent than FABP1, but also binds ECs), and decreased degradative enzymes (NAAA, MAGL). These data indicated that FABP1 is not only the most prominent endocannabinoid and cannabinoid binding protein, but also impacts hepatic endocannabinoid levels.

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Section: Resultsmentioning

confidence: 99%

FABP1: A Novel Hepatic Endocannabinoid and Cannabinoid Binding Protein

Huang¹,

McIntosh²,

Martin³

et al. 2016

Biochemistry

154

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“…Hepatic CB1 (and CB2) are markedly upregulated in non-alcoholic liver disease (NAFLD) (101–103), while CB1 is upregulated in alcoholic liver disease (AFLD) (102, 104) and in response to high-fat diet-induced obesity (102, 104). Concomitantly, hepatic AEA and 2-AG levels are also elevated in NAFLD, while 2-AG (but not AEA) is elevated in AFLD, and AEA (but not 2-AG) is elevated in response to high-fat diet (101–104).…”

Section: Human and Murine Fabp1 Impact Liver Endocannabinoidsmentioning

confidence: 99%

Fatty Acid Binding Protein‐1 (FABP1) and the Human FABP1 T94A Variant: Roles in the Endocannabinoid System and Dyslipidemias

Schroeder

McIntosh

Martin

et al. 2016

Lipids

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The first discovered member of the mammalian FABP family, liver fatty acid binding protein (FABP1, L-FABP), occurs at high cytosolic concentration in liver, intestine and in the case of humans also in kidney. While the rat FABP1 is well studied, the extent these findings translate to human FABP1 is not clear—especially in view of recent studies showing that endocannabinoids and cannabinoids represent novel rat FABP1 ligands and FABP1 gene ablation impacts the hepatic endocannabinoid system, known to be involved in non-alcoholic fatty liver (NAFLD) development. Although not detectable in brain, FABP1 ablation nevertheless also impacts brain endocannabinoids. Despite overall tertiary structure similarity, human FABP1 differs significantly from rat FABP1 in secondary structure, much larger ligand binding cavity, and affinities/specificities for some ligands. Moreover, while both mouse and human FABP1 mediate ligand induction of peroxisome proliferator activated receptor-α, (PPARα), they differ markedly in pattern of genes induced. This is critically important because a highly prevalent human SNP (26–38% minor allele frequency and 8.3±1.9% homozygous) results in a FABP1 T94A substitution that further accentuates these species differences. The human FABP1 T94A variant is associated with altered body mass index (BMI), clinical dyslipidemias (elevated plasma triglycerides and LDL cholesterol), atherothrombotic cerebral infarction, and non-alcoholic fatty liver disease (NAFLD). Resolving human FABP1 and the T94A variant’s impact on the endocannabinoid and cannabinoid system is an exciting challenge due to the importance of this system on hepatic lipid accumulation as well as behavior, pain, inflammation, and satiety.

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“…Cannabinoid-1 receptor (CB1), which responds to cannabinoids that increase fat intake, regulates the activity of these lipogenic and lipolytic transcription factors [6, 7], and the intake of ethanol and high-fat diet induce upregulation of CB1 activity through increased synthesis of endocannabinoids, 2-AG, and anandamide [1]. Because CB1 is also upregulated in obesity, CB1 is a potential therapeutic target for obesity and NAFLD [8].…”

Section: Introductionmentioning

confidence: 99%

Exercise without dietary changes alleviates nonalcoholic fatty liver disease without weight loss benefits

Bae

2018

Lipids Health Dis

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BackgroundThis study aimed to analyze the effect of exercise and/or dietary change on improvement of non-alcoholic fatty liver disease (NAFLD) in chronic high-fat diet (HFD)-induced obese mice.MethodsForty male C57BL/6 (8 weeks old) mice were divided into normal diet (CO, n = 8) and high-fat diet (HF, n = 32) groups. The HF group was fed with 60% fat chow for 16 weeks to induce obesity. After the obesity induction period, the HF group was subdivided into HFD + sedentary (n = 8), HFD + training (HFT, n = 8), dietary change to normal-diet + sedentary (HFND, n = 8), and dietary change to normal-diet + training (HFNDT, n = 8) groups, and the mice in the training groups underwent treadmill training for 8 weeks, 5 times per week, 40 min per day.ResultsA 24-week HFD induced increase of cannabinoid-1 receptor (CB1), fatty acid synthase (FAS), and AMP-activated protein kinase (AMPK) protein expressions (p < 0.05) and decrease of p-AMPK and carnitine palmitoyltransferase1 (CPT1) protein expressions (P < 0.05), resulting in increased liver fat accumulation. Treatment of exercise with dietary change and dietary change alone decreased CB1 and AMPK protein expressions with increased p-AMPK and CPT1 protein expressions (P < 0.05), leading to decreased body weight and liver fat (P < 0.05). The CB1 and FAS protein expressions in the HFT group were still higher than those in the CO group (P < 0.05), but the p-AMPK and CPT1 protein expressions were higher than those in the HF group (P < 0.05). Moreover, improved glucose tolerance and decreased liver fat were confirmed, although treatment of exercise alone had no effect on weight loss compared to pre-exercise.ConclusionsEven in the case of obesity induced by chronic HFD, exercise and/or dietary interventions have preventive and therapeutic effects on fat accumulation in the liver, resulting from upregulations of lipolytic factors. Therefore, the results of this study suggested that treatment of exercise alone without dietary change also leads to improvement of NAFLD and glucose tolerance without weight loss benefits.

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Cannabinoid 1 receptor in fatty liver

Cited by 15 publications

References 87 publications

FABP1: A Novel Hepatic Endocannabinoid and Cannabinoid Binding Protein

FABP1: A Novel Hepatic Endocannabinoid and Cannabinoid Binding Protein

Fatty Acid Binding Protein‐1 (FABP1) and the Human FABP1 T94A Variant: Roles in the Endocannabinoid System and Dyslipidemias

Exercise without dietary changes alleviates nonalcoholic fatty liver disease without weight loss benefits

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