Potential Mechanisms Influencing the Inverse Relationship Between Cannabis and Nonalcoholic Fatty Liver Disease: A Commentary

Abstract

Nonalcoholic fatty liver disease (NAFLD) develops when the liver is unable to oxidize or export excess free fatty acids generated by adipose tissue lipolysis, de novo lipogenesis, or dietary intake. Although treatment has generally been centered on reversing metabolic risk factors that increase the likelihood of NAFLD by influencing lifestyle modifications, therapeutic modalities are being studied at the cellular and molecular level. The endocannabinoid system has been of recent focus. The agonism and antagonism of cannabinoid receptors play roles in biochemical mechanisms involved in the development or regression of NAFLD. Exocannabinoids and endocannabinoids, the ligands which bind cannabinoid receptors, have been studied in this regard. Exocannabinoids found in cannabis (marijuana) may have a therapeutic benefit. Our recent study demonstrated an inverse association between marijuana use and NAFLD among adults in the United States. This commentary combines knowledge on the role of the endocannabinoid system in the setting of NAFLD with the findings in our article to hypothesize different potential mechanisms that may influence the inverse relationship between cannabis and NAFLD.

Comment on: Kim D, Kim W, Kwak MS, Chung GE3, Yim JY, Ahmed A. Inverse association of marijuana use with nonalcoholic fatty liver disease among adults in the United States. PLoS One. 2017 Oct 19;12(10):e0186702. DOI: 10.1371/journal.pone.0186702. PubMed PMID: 29049354. https://www.ncbi.nlm.nih.gov/pubmed/29049354.

Nonalcoholic fatty liver disease (NAFLD) is defined as hepatic steatosis in the absence of other known etiologies of hepatic injury such as significant alcohol consumption, viral hepatitis, metabolic/genetic disorders, and steatogenic medication use.¹ The histologic spectrum of NAFLD constitutes nonalcoholic fatty liver (NAFL), nonalcoholic steatohepatitis (NASH), advanced fibrosis, and cirrhosis.¹ The prevalence of NAFLD varies in the literature but has been estimated to be up to 30% of the world’s population.¹ The clinical burden of NAFLD is projected to rise over the next decade and result in significant economic burden, largely attributed to the increasing prevalence of diabetes and obesity compounded by a lack of treatment.²,³ Currently, there is no approved pharmacologic treatment for NAFLD. Patients are left with the challenge of “life style modifications,” which are difficult to maintain in an effective and sustained fashion.³ Therefore, there is an unmet need to find new treatment target(s) for NAFLD.³,⁴ The endocannabinoid system may mechanistically provide a potential therapeutic target to treat patients with NAFLD. In fact, our population-based study using a national registry from the United States suggested an inverse association between marijuana use and NAFLD. A clear understanding of the pathophysiology of NAFLD plays an important role in the assessment of such therapeutic agents.

To briefly review, hepatic steatosis occurs when the liver is unable to oxidize or export free fatty acids resulting from adipose tissue lipolysis, de novo lipogenesis, or dietary intake.⁵,⁶ Free fatty acids may overburden the liver from lipolyzed adipose triacylglycerol or dietary lipids, or there may be increased de novo lipogenesis in the setting of reduced hepatic fatty acid oxidation.⁷ Insulin resistance is the central underlying mechanism that triggers the pathogenesis of NAFLD by increasing insulin levels and free fatty acid influx into the liver, promoting hepatic triglyceride synthesis, and stimulating secretion of very low-density lipoprotein (VLDL).⁸,⁹ In addition, there may be a reduction in the ability of insulin to suppress peripheral lipolysis.⁹ Visceral adipose tissue has also been implicated, which can expand and cause adipocyte hypertrophy associated with increased cytokines and adipokines, such as adiponectin, leptin, tumor necrosis factor-alpha (TNF-α), and interleukin-6.⁵ Therefore, the role of insulin resistance in NAFLD may be the pathophysiologic mechanism in the association of marijuana use and NAFLD.¹⁰

In our data using a nationally representative sample from the United States, we demonstrated that cannabis use was inversely associated with the prevalence of NAFLD in models that were adjusted for age, gender, and ethnicity.¹⁰ Data were also adjusted for body mass index, diabetes, and hypertension (known risk factors for NAFLD). Furthermore, variables such as education level, economic status, smoking status, alcohol consumption, and current use of cocaine, heroin, and/or amphetamine were also assessed.¹⁰ We demonstrated that current or past marijuana use was associated with a lower risk of NAFLD.¹⁰ These findings may coincide with some current literature that proposes that the endocannabinoid system plays a role in NAFLD. Within the endocannabinoid system, cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2) are receptors bound by lipophilic ligands called endocannabinoids and exogenous ligands called exocannabinoids.⁶ Cannabinoid receptor 1 is primarily found in the brain but has been found in endothelial cells and hepatocytes.⁶ Cannabinoid receptor 2 is found in the peripheral tissue and has been detected in Kupffer cells.⁶ Agonism of CB1 is associated with increased de novo lipogenesis, decreased fatty acid oxidation, increased lipogenic gene expression, activation of lipoprotein lipase, and decreased secretion of VLDL.¹¹,¹² Antagonism of CB1 has demonstrated an overall improvement in metabolic syndrome by reducing caloric intake and increasing energy expenditure in animal models.¹³ In animal models, CB1 antagonism also inhibited de novo lipogenesis.¹⁴ The CB1 antagonist, rimonabant, demonstrated reduced hepatomegaly and hepatic steatosis, improved markers of liver damage, and reduced hepatic TNF-α.¹⁵ The literature regarding CB2 agonism and antagonism is conflicting.¹³,¹⁶,¹⁷

Endocannabinoids are endogenous ligands and include anandamide (arachidonoyl ethanolamide [AEA]) and 2-arachidonoyl glycerol (2-AG).⁶ Exocannabinoids, however, are components of cannabis and include tetrahydrocannabinol (THC), tetrahydrocannabivarin (THCV), and cannabidiol (CBD).¹⁸,¹⁹ These exocannabinoids vary in amounts per strain of cannabis.²⁰ Endocannabinoids function by activating CB1 and CB2.⁶ Exocannabinoids vary in terms of function. THC acts on CB1 and CB2¹⁸ and may increase AEA and 2-AG.²¹ Cannabidiol functions as an antagonist of CB1 and CB2.²² However, the function of THCV, which is an analog of THC, is dose-dependent; in high doses, it is a neutral antagonist of CB1 and CB2, and in low doses, it is an agonist of CB1 and a partial agonist of CB2.²² Endocannabinoids are increased by steatogenic agents and potentiate CB1, which suggests that they may promote the pathogenesis of NAFLD.¹² Exocannabinoids, however, yield unclear results. Exocannabinoids in cannabis have anti-inflammatory effects by inhibiting cytokines, which may be protective against NAFLD.²³,²⁴ The partial antagonist action of the nonpsychotropic exocannabinoid, CBD, on CB1 receptor may improve insulin sensitivity, which may offer a prudent approach in the development of drugs for the management of NAFLD. On the contrary, by activating CB1, THC should theoretically induce or worsen NAFLD. However, our data suggested that cannabis, composed of THC among other exocannabinoids, was independently associated with a lower risk of NAFLD.¹⁰ Therefore, tolerance of CB1 from repetitive THC use may be the mechanism behind the inverse relationship that was noted in our study population. Repeated use of THC may result in decreased CB1 density, which may account for the dose-dependent relationship between marijuana and NAFLD exhibited in our study.²²,²⁵ Cannabidiol and THCV can act as CB1 antagonists and may hypothetically reduce hepatic steatosis, hepatomegaly, markers of liver damage, and cytokines, while improving metabolic syndrome.²²

The ambiguity and conflicting hypotheses as to pathogenetic mechanisms in the relationship between marijuana and NAFLD warrant further research and investigation. Perhaps the exact amount of cannabis used and the strain of cannabis used as related to its chemical content may clarify which exocannabinoids are responsible for the beneficial and/or harmful effects related to the pathogenesis of NAFLD. With this knowledge, further investigation can be done to delineate whether agonism and/or antagonism of either of the cannabinoid receptors predominate. It is important to consider that the inverse relationship between cannabis and NAFLD may be secondary to known anti-inflammatory properties of cannabis alone or in conjunction with modulation of the receptors. Nonetheless, the endocannabinoid system can be promising therapeutic target to treat NAFLD at the cellular and molecular level.