Excessive, chronic alcohol consumption can lead to alcoholic liver disease. The etiology of alcoholic liver disease is multifactorial and is influenced by alterations in gene expression and changes in fatty acid metabolism, oxidative stress, and insulin resistance. These events can lead to steatosis, fibrosis, and eventually to cirrhosis and liver cancer. Many of these functions are regulated by peroxisome proliferator-activated receptors (PPARs). Thus, it is not surprising that PPARs can modulate the mechanisms that cause alcoholic liver disease. While the roles of PPARα and PPARγ are clearer, the role of PPARβ/δ in alcoholic liver disease requires further clarification. This review summarizes the current understanding based on recent studies that indicate that PPARβ/δ can likely be targeted for the treatment and/or the prevention of alcoholic liver disease.

Fatty liver disease is caused by many mechanisms, including those induced by dietary, genetic, and environmental factors. For example, obesity is strongly associated with fatty liver disease in the absence of alcohol exposure.¹⁾ Alcohol consumption is also a major cause of hepatic diseases worldwide, including fatty liver disease.²⁾ Alcohol abuse often causes injury in the liver, leading to a condition known as alcoholic liver disease. Alcoholic liver disease is characterized by excessive lipid accumulation, oxidative stress, lipid peroxidation, acetaldehyde toxicity, fibrosis, and ultimately damage to the functional hepatocytes.^2–9) The disease is complex because in addition to alcohol consumption, other factors can also contribute to the etiology of alcoholic liver disease including obesity, dyslipidemias, and insulin resistance can also contribute to alcoholic liver disease pathogenesis.^10–16)

Alcoholic liver disease includes two stages: the reversible early stage and the irreversible late stage (Fig. 1). During the early stage, alcohol consumption leads to steatosis (lipid accumulation); a reversible process. This was demonstrated in studies showing that abstinence from alcohol led to the amelioration of hepatic lesions^17–19) This is important to note because lipid accumulation in the liver is regulated by both biosynthesis and degradation of fatty acids and other lipids, so there is a balance likely achieved through homeostatic mechanisms. If a patient with alcoholic liver disease at the early phase does not undergo treatment or does not receive the appropriate treatment to prevent or stop the early changes in hepatic metabolism, the disease can progress to the late phase that leads to alcoholic hepatitis, fibrosis, and cirrhosis, and potentially progression to hepatocellular carcinoma.^2,20) (Fig. 1). Early alcoholic liver disease-specific diagnosis and treatment are important because there are widely variable metabolic pathways modulated during the early stage versus late stage of alcoholic liver disease that will dictate the most appropriate molecular target or targets for the prevention and/or progression to the irreversible, late stage of alcoholic liver disease (Fig. 1).

Fig. 1. Hypothetical Mechanism How PPARβ/δ Suppresses Alcoholic Liver Disease

Alcohol consumption alters fatty acid metabolism, lipid accumulation, and insulin resistance causing steatosis during the early stages, that culminates with fibrosis, cirrhosis and potentially liver cancer during the late stages. The early stages of alcoholic liver disease are potentially reversible by targeting with PPARβ/δ agonists that can mitigate some of the changes induced by alcohol including increasing fatty acid catabolism, improving insulin resistance and limiting or reversing lipid accumulation. (Color figure can be accessed in the online version.)

Peroxisome proliferator-activated receptors (PPARs) are part of the nuclear receptor superfamily 1C of ligand-inducible transcription factors. PPARs have three subtypes, (PPARα or NR1C1, PPARβ/δ or NR1C2, and PPARγ or NR1C3).^21,22) PPARs are recognized as lipid sensors and central regulators of lipid metabolism.^23,24) The specificity of PPAR function is regulated at many levels including their tissue and subcellular distribution and the relative bioavailability of endogenous and exogenous ligands. PPARα is expressed at high levels in organs with active fatty acid metabolism, including the liver and kidney.^25,26) PPARγ is expressed in adipose tissues and organs of the immune system.²⁶⁾ Like all PPARs, PPARβ/δ is expressed in many tissues, but with notably higher expression in the intestine, liver, and keratinocytes.^27,28) PPARs are regulated in dynamic fashion. In other words, PPARs are typically active (or not) in all cells due to the presence/absence of endogenous ligands that fluctuate in tissue concentration due to normal homeostatic changes. (e.g. the flux of non-esterified fatty acids from adipose to liver increases during periods of starvation but decreases after feeding).²⁹⁾ When PPARs are activated by a ligand, the receptor forms a heterodimer with the retinoid X receptor (RXR) and other regulatory proteins. The PPAR:RXR complex recognizes response elements in target gene promoters and increases or decreases the expression of proteins that regulate lipid metabolism.³⁰⁾ Through this highly conserved mechanism, PPARα primarily regulates fatty acid metabolism and energy metabolism in the liver,³¹⁾ whereas PPARγ plays an important role in adipogenesis and inflammation.³²⁾ The potential role of PPARs for preventing or treating alcoholic liver disease has been illustrated more extensively for PPARα and PPARγ.³³⁾ However, recent findings suggest that PPARβ/δ also contributes to alcoholic liver disease. This review highlights the critical roles of PPARβ/δ in the pathogenesis of alcoholic liver disease and discusses the potential molecular mechanisms involved.

Since PPARs function through well conserved molecular mechanisms and there is overlap in the target genes regulated by PPARs, it is important to note the distinctions between different PPARs and how they might be targeted for preventing or treating alcoholic liver disease. Studies on the relationship between alcoholic liver disease and PPARs are typically performed with Ppar-null rodents to evaluate the effects of PPAR ablation on alcoholic liver disease development, or using specific agonists/antagonists to elucidate the effects of the transcriptional activity of PPARs on alcoholic liver disease. However, the effect of alcohol on PPAR expression remains controversial because there are differences reported in the literature. For example, some studies suggest that alcohol consumption suppresses PPARα expression compared to controls,^34–37) whereas others have shown that change in PPARα expression in response to alcohol does not occur.^38,39) The reasons for the differences in findings remains unclear; however, these differences could be attributed to the differences in experimental procedures, animal species, sex, or age, and the time course of alcohol administration.

Expression of PPARα is relatively high in hepatocytes and for this reason could be considered the primary PPAR subtype linked with alcoholic liver disease. The relationship between PPARα and alcoholic liver disease has been investigated in several studies and discussed previously.^40–42) Excessive alcohol consumption induces oxidative stress and inflammation and disrupts fatty acid metabolism.^7,43) Moreover, alcohol consumption has been shown to impair expression and transcriptional activity of PPARα.^34,44–46) Ligand activation of PPARα also inhibits oxidative stress, inflammation, and promotes fatty acid catabolism thereby decreasing hepatic and serum lipids that are known risk factors for alcoholic liver disease.^47–50) Thus, it is not surprising that Ppara-null mice exhibit exacerbation of alcoholic liver injury and that ligand activation of the PPARα prevents alcoholic liver injury.^44,45,51)

PPARγ is expressed at relatively low levels in the liver compared to adipose tissue but is still important for nutrition-based hepatic diseases.³²⁾ Activation of PPARγ improves insulin sensitivity, but strikingly increases adipogenesis and lipid accumulation in the liver.^52–54) Interestingly, expression of PPARγ is elevated in a mouse model of hepatic steatosis.^55–58) Genetic silencing of PPARγ suppresses alcohol-induced liver injury and lipid accumulation.⁵⁹⁾ This suggests that PPARγ promotes alcoholic liver disease; however, the mechanisms underlying this possibility remains unclear. Alcohol activates PPARγ and its target gene, monoacylglycerol O-acyltransferase 1, which catalyses triglyceride synthesis.⁶⁰⁾ In addition, alcohol consumption can accelerate reverse cholesterol transport by PPARγ and the high density lipoprotein receptor scavenger receptor class B type I.³⁹⁾ This suggests that PPARγ promotes alcoholic liver disease by accelerating lipid accumulation in the liver and/or increased hepatic lipid synthesis. Therefore, the role of PPARγ in the mechanism underlying alcoholic liver disease remains controversial, as some studies suggest that activation of the PPARγ may prevent or inhibit alcohol-induced steatohepatitis whereas others indicate activation of the PPARγ promotes alcohol-induced steatohepatitis.^61,62) These differences could be due to the models examined since some were based on genetic silencing versus activation of the PPARγ. Thus, the role of PPARγ in the etiology of alcoholic liver disease requires further examination.

Expression and/or ligand activation of PPARβ/δ can protect against chemically-induced liver injury through multiple mechanisms, including promotion of fatty acid catabolism, or inhibition of nuclear factor-kappa B (NF-κB)-dependent pro-inflammatory signalling.^12,63–65) For example, Pparb/d-null mice exhibit enhanced activity of hepatic NF-κB-dependent pro-inflammatory signaling in response to exposure to liver toxicants,⁶³⁾ and ligand activation of PPARβ/δ prevents this inhibition by interfering with pro-inflammatory signaling in the liver.⁶⁴⁾ Moreover, there is strong evidence from multiple models that ligand activation of PPARβ/δ inhibits a number of molecular targets that prevent non-alcoholic fatty liver disease.⁶⁶⁾ Given these observations, it is not surprising that there is also evidence from different models indicating that PPARβ/δ may be preventive and/or therapeutic for alcoholic liver disease, similar to its role in hepatotoxicity. In this section, we summarize how PPARβ/δ might be targeted at different molecular levels for the prevention or treatment of alcoholic liver disease.

Hepatic steatosis is caused by excess dietary fat, increased release of fatty acids from adipose tissue, increased fatty acid synthesis, suppression of fatty acid catabolism, and/or inhibition of lipid export from the liver. Thus, suppressing fatty acid synthesis and increasing fatty acid catabolism are central targets for preventing or treating hepatic steatosis that contributes to the etiology of alcoholic liver disease.²⁾ Consumption of alcohol accelerates the biosynthesis of hepatic fatty acids, triglycerides, and phospholipids during the early stage of alcoholic liver disease (Fig. 1) by upregulating lipogenic enzymes such as fatty acid synthase, acyl CoA carboxylase, ATP-citrate lyase, and stearoyl-CoA desasturase.^67–69) The expression of these lipogenic proteins is regulated by sterol-regulatory element binding proteins (SREBPs).^70,71) Notably, ligand activation of PPARβ/δ inhibits the activity of SREBPs, in particular SREBP-1. Ligand activation of PPARβ/δ inhibits the lipogenic action of SREBP-1 by directly increasing the expression of insulin-induced gene-1 (Insig-1), which in turn prevents the cleavage of SREBP-1c.⁷²⁾ By contrast, genetic silencing of PPARβ/δ increases SREBP-1 activity without suppressing Insig-1 expression.⁷³⁾ These results collectively demonstrate that PPARβ/δ regulates SREBP-1 activity and hepatic lipogenesis. The relationship between PPARβ/δ and hepatic lipid accumulation in alcoholic liver disease has been also been examined. Ligand activation of PPARβ/δ suppresses alcohol-induced hepatic lipid accumulation.^74,75) Consistent with these findings, PPARβ/δ ablation enhances hepatic triglyceride accumulation in response to alcohol consumption.⁷³⁾ These findings suggest that PPARβ/δ can inhibit hepatic steatosis caused by excess alcohol intake.

It is well established that ligand activation of PPARα promotes hepatic fatty acid oxidation and a decrease in hepatic lipid accumulation because PPARα increases the expression of numerous proteins that regulate the release of endogenous fatty acids, transport of fatty acids to the liver for oxidation, transport across cellular membranes, and oxidative degradation of fatty acids in the mitochondria and peroxisomes.^76,77) However, there is also good evidence that ligand activation of PPARβ/δ can also promote fatty acid catabolism and be a potential target for alcoholic liver disease. For example, it is known that ligand activation of PPARβ/δ increases skeletal muscle fatty acid catabolism by increasing expression of proteins that facilitate this metabolic change.⁷⁸⁾ Since alcohol consumption inhibits fatty acid catabolism in the liver.⁴³⁾ it is of interest to note that alcohol inhibits fatty acid metabolism in hepatocytes by inhibiting PPARα, a major regulator of genes that encode proteins associated with free fatty acid transport and oxidation, including carnitine palmitoyltransferase 1 (CPT-1).²⁾ CPT-1 is a transporter protein located on the mitochondrial membrane to facilitate fatty acid transport across this membrane.⁷⁹⁾ In addition, PPARα also regulates expression of carnitine-acylcarnitine translocase (CAC T) a protein that facilitates fatty acid transport across the mitochondrial membrane.⁸⁰⁾ CPT-1 is located on the outer membrane of the mitochondria, whereas CAC T is located in the inner membrane.⁸¹⁾ CPT-1 and CAC T are components of the carnitine cycle and play an important role in the transfer of fatty acids from the cytosol to the mitochondria for subsequent fatty acid metabolism. Thus, it is not surprising that PPARβ/δ can also regulate fatty acid metabolism in the liver as well as peripheral tissues.^82–85) These observations collectively suggest that PPARβ/δ can modulate hepatic fatty acid degradation that is known to become dysregulated in response to alcohol intake.⁴³⁾ Importantly, activation of the PPARβ/δ ligand induces CPT-1 and CAC T expression in hepatic cells, similar molecular targets for the PPARα.⁸⁰⁾ This indicates that PPARβ/δ has overlap in the regulation of hepatic fatty acid degradation with PPARα, and ancillary regulation of skeletal muscle fatty acid degradation independent of PPARα.

An autophagy-mediated pathway was recently reported to promote fatty acid catabolism and attenuate hepatic steatosis by activation of PPARβ/δ.⁸⁶⁾ Tong et al showed that PPARβ/δ increases AMP-activated protein kinase (AMPK) phosphorylation, inhibiting mammalian target of rapamycin (mTOR) as a nutrient-sensing kinase. Through this mechanism, PPARβ/δ-AMPK-mTOR pathway facilitates fatty acid turnover via the activation of the autophagy-lysosomal pathway.⁸⁶⁾ Autophagy is usually activated in response to nutrient deprivation and other intracellular stresses that promote cell survival. These studies indicate that in addition to the known role of autophagy in promoting oxidative stress and cell turnover, autophagy can also impact lipid droplet accumulation and mitochondrial damage causing changes in hepatic fatty acid metabolic pathways in response to ligand activation of PPARβ/δ. This is important because there is accumulating evidence indicating that alcohol consumption inhibits autophagy and promotes apoptosis in the liver,^87–89) Further studies are needed to determine whether suppression of lipid accumulation in alcoholic liver disease via PPARβ/δ is dependent on autophagy.

Insulin is an important hormone and controls various physiological functions. One important action of insulin in the liver is the suppression of gluconeogenesis via the insulin receptor substrate 2 (IRS2) pathway and the regulation of lipogenesis via the IRS1 pathway. The IRS1 pathway induces expression of SREBP-1 and promotes de novo lipid synthesis in the liver and dysfunction of this pathway can cause insulin resistance.⁹⁰⁾ Insulin resistance is the hallmark of metabolic syndrome and diabetes characterized by high serum glucose and triglycerides levels due to impaired insulin responsiveness in target tissues.⁹¹⁾ Given the effects of insulin resistance, it is not surprising that insulin resistance is causally linked to diabetes, dyslipidemias, cardiovascular disease, and exacerbated hepatic steatosis.^92–94) In the liver, insulin resistance prevents the suppression of gluconeogenesis and promotion of lipid synthesis, which further enhances hepatic lipid accumulation.^95,96)

The effect of alcohol consumption on insulin resistance remains unclear.^97,98) There is evidence suggesting that alcohol disturbs insulin resistance by promoting accumulation of ceramides.⁹⁹⁾ Alcohol consumption promotes accumulation of hepatocyte ceramides in the endoplasmic reticulum, thereby leading to endoplasmic reticulum stress and insulin resistance.¹⁰⁰⁾ Since ligand activation of PPARβ/δ does not affect alcohol-induced accumulation of ceramides,⁷⁴⁾ PPARβ/δ does not appear to modulate insulin resistance via ceramide accumulation. Interestingly, ceramides contain fatty acids with varying chain lengths and a ceramide containing a C18 saturated fatty acid was required for regulating insulin resistance, whereas ceramides with fatty acids of longer or shorter chain lengths were not.¹⁰¹⁾ Unfortunately, studies that have examined the relationship between alcohol intake, ceramide content, and activity of PPARβ/δ have not focused on the fatty acid present within ceramides but rather the total ceramide content in the tissue. Thus, the types of ceramides that accumulate in the liver of patients with alcoholic liver disease should be examined. Given the known critical role of PPARβ/δ in regulating glucose homeostasis,⁸²⁾ targeting this pathway by activation of PPARβ/δ remains a viable approach that should be examine in greater detail for the prevention and treatment of alcoholic liver disease.

Interleukin 6 (IL-6) is a cytokine secreted during inflammation but is also known to modulate insulin resistance.¹⁰²⁾ IL-6 induces insulin resistance by activation of signal transducer and activator of transcription 3 (STAT3) and the subsequent induction of suppressor of cytokine signaling 3.^103–105) In addition, the IL-6/STAT3 pathway was also reported to be regulated by AMPK a central sensor of energy homeostasis.¹⁰⁶⁾ Ligand activation of PPARβ/δ improves insulin resistance⁸²⁾ and attenuates alcohol-induced insulin resistance¹¹⁾ by increasing AMPK activity,^84,85) which leads to the attenuation of insulin resistance via the IL-6/STAT3 pathway.¹⁰⁷⁾ Collectively, these results suggest that ligand activation of PPARβ/δ suppresses insulin resistance caused by alcohol consumption in part by activation of the AMPK pathway.

The liver is most susceptible to alcohol abuse, as it is the primary site for alcohol metabolism.^108,109) In the liver, alcohol is metabolized to acetaldehyde by alcohol dehydrogenase and CYP2E1.^110–112) Acetaldehyde is a reactive and toxic metabolite and considered a major resource for the generation of reactive oxygen species (ROS) in alcohol metabolism.^113,114) ROS can react with cellular components, causing cell injury by oxidative stress that leads to altered cellular functions.^110,115) Therefore, ROS generation is another key factor in the etiology of alcoholic liver disease. CYP2E1 is one enzyme linked with the mechanisms causing alcoholic liver disease, because alcohol induces CYP2E1 expression that promotes ROS production and oxidative damage.¹¹⁶⁾ Consistent with this notion, genetic ablation of CYP2E1 was shown to suppress alcohol-induced lipid accumulation and liver injury in mice.^36,117) Since genetic ablation of PPARβ/δ causes enhanced expression of CYP2E1 in response to alcohol consumption, this indicates that PPARβ/δ might suppress alcohol-induced CYP2E1 expression suggesting that this mechanism inhibits the production of hepatic ROS that can cause intracellular damage.⁷³⁾

Hepatic expression of CYP2B is also increased in response to alcohol consumption.^118,119) Five isoforms of CYP2B are expressed in mice, CYP2B9, CYP2B10, CYP2B13, CYP2B19, and CYP2B23, whereas only one isoform, CYP2B6, is expressed in humans.^120–122) Of these CYP2B isoforms, CYP2B9, CYP2B10 and CYP2B13, are primarily expressed in the liver.^121,123,124) CYP2B expression is regulated by the chemically-activated nuclear receptors constitutive androstane receptor (CAR) and pregnane X receptor (PXR).^{123,125–130)} Ligand activation of the CAR or PXR induces CYP2B expression, and both receptors can mediate these changes in CYP2B.^{123,128,130,131)} CYP2B10 is thought to function like a drug-metabolizing enzyme, similar to human CYP2B6.¹³⁰⁾ In addition, proteins of the CYP2B subfamily may have roles in obesity and hepatic steatosis linked with unsaturated fatty acid metabolism.^132,133) Indeed, genetic ablation of CYP2B increases susceptibility to obesity and promotes the severity of hepatic steatosis.¹³⁴⁾ This indicates that the induction of CYP2B isoforms protects against alcohol toxicity by regulation of fatty acid metabolism. Indeed, CYP2B10 has a major role in controlling fatty acid homeostasis in response to activation of CAR-dependent transcriptional regulation.¹³³⁾ Surprisingly, PPARβ/δ ablation suppresses alcohol-induced hepatic CYP2B10 expression and this effect is not dependent on CAR.¹³⁵⁾ It remains unclear how PPARβ/δ regulates CYP2B10 expression and whether/how PPARβ/δ interacts with the transcriptional activity of CAR. Further studies are needed to determine how PPARβ/δ suppresses alcohol-induced expression of CYP2B10.

Combined, these observations suggest that PPARβ/δ has a protective role in alcoholic liver disease by controlling expression of hepatic CYPs. The induction of CYP2E1 by alcohol promotes alcoholic liver disease, whereas the induction of CYP2B10 by alcohol suppresses alcoholic liver disease.

Alcoholic liver disease is associated with dysregulated bile acid homeostasis and gut barrier function.^2,136,137) Chronic alcohol consumption causes an increase in the total bile acid pool in the liver and serum bile acids, however, ligand activation of PPARβ/δ with a selective ligand reverses this phenotype.¹³⁸⁾ Moreover, chronic alcohol consumption causes disruption of the gut barrier function and ligand activation of PPARβ/δ with a selective ligand also reverses this phenotype.¹³⁸⁾ These observations were noted in studies examining the both preventive and the therapeutic effects of activating PPARβ/δ in alcoholic liver disease.^136–138) Interestingly, results from these studies also suggest that these changes in bile acid homeostasis and gut barrier function caused by alcohol consumption are due in part to alterations in the gut microbiota.

PPARβ/δ is known to have important homeostatic roles in the fundamental regulation of lipid and glucose metabolism, differentiation, and inflammation.^139–141) There is strong evidence shows that PPARβ/δ inhibits the development of nonalcoholic fatty liver disease.⁶⁶⁾ It is thus not surprising that targeting PPARβ/δ for the prevention and/or treatment of alcoholic liver disease is likely feasible. Mechanistically, this is mediated by PPARβ/δ-dependent regulation of: 1) hepatic lipid accumulation due to both anabolic and catabolic pathways, 2) insulin resistance, 3) inflammation, and 4) bile acid pools and gut barrier function. Whereas alcoholic liver disease can be suppressed by abstinence from alcohol in the early stage (Fig. 1), this is not true for the late stage. Interestingly, activation of PPARβ/δ does not affect preference of alcohol, whereas ligand activation of PPARα and PPARγ can reduce alcohol consumption.^142,143) However, ligand activation of PPARβ/δ suppresses alcoholic liver disease as noted in this review. These facts suggest that ligand activation of PPARβ/δ could be a preventive and/or therapeutic target for alcoholic liver disease through a mechanism that is not based on abstinence or reduced intake, but rather on molecular pathways that mediate the etiology of alcoholic liver disease. Given that several PPARβ/δ ligands have been developed and examined in the clinic for treating non-alcoholic liver disease (e.g. KD-3010, seladelpar),⁶⁶⁾ there is good reason to suggest that targeting PPARβ/δ for the prevention and treatment of alcoholic liver disease provides a novels approach for this disease that impacts millions of humans (Fig. 1).

The authors declare no conflict of interest.

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