Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2023 Aug 1.
Published in final edited form as: Alcohol. 2022 Apr 19;102:51–57. doi: 10.1016/j.alcohol.2022.04.001

Elevated Stearoyl-CoA Desaturase 1 Activity is associated with Alcohol-associated Liver Disease

TD Klepp 1, ME Sloan 2,3,4,5,6,7, Soundarya Soundararajan 2, CE Ramsden 8, R Cinar 9, ML Schwandt 1, N Diazgranados 1, V Vatsalya 2,10,11,✉, VA Ramchandani 2,✉
PMCID: PMC9256783  NIHMSID: NIHMS1801186  PMID: 35452750

Abstract

Chronic binge drinking induces hepatic lipid accumulation, but only certain individuals develop alcohol-associated liver disease (ALD). Specific patterns of lipid accumulation are thought to be associated with ALD, but this has not been comprehensively investigated to date. We analyzed plasma fatty acid levels quantified by gas chromatography-mass spectrometry in a sample of patients with alcohol use disorder (AUD). Given that elevation in serum alanine aminotransferase (ALT) levels are strongly associated with ALD, patients were stratified into two groups based on ALT levels: an ALD group (ALT > 40 IU/L) and a non-ALD group (ALT ≤ 40 IU/L). There was a shift towards greater concentrations of monounsaturated fatty acids in the ALD group compared to the non-ALD group. Steroyl-CoA desaturase (SCD1) activity in the ALD group was then estimated as the ratio of palmitoleic acid (16:1) to palmitic acid (16:0). SCD1 activity was greater in the ALD than the non-ALD group. A series of linear regression models demonstrated that SCD1 activity mediated the association between binge drinking and ALD. These findings provide initial evidence that SCD1 activity may be associated with ALD. If validated prospectively, elevated SCD1 activity could potentially be used as a biomarker to identify individuals at high risk for developing ALD.

Keywords: Alcohol-Associated Liver Disease, Fatty Acids, Palmitoleic Acid, Stearoyl-CoA Desaturase, Alcohol Use Disorder, Binge Drinking

INTRODUCTION

Chronic binge drinking can result in alcohol-associated liver disease (ALD) ranging in severity from fatty liver to alcohol-associated hepatitis to cirrhosis (1). This is a major public health concern, as approximately 50% of cases of cirrhosis have been attributed to alcohol misuse (2). While alcohol consumption is a leading risk factor for both hepatitis and cirrhosis, a significant proportion of binge drinkers develop end-stage ALD (3). Elucidating the risk factors and the biological underpinnings of development and progression of ALD could facilitate the identification of individuals at risk of developing of both the early and advanced stages of ALD and help us identify molecular targets for treatment.

The present study aims to characterize lipidomic shifts in ALD in order to determine whether changes in specific enzymatic pathways differentiate binge drinkers with and without ALD. Shifts in lipid accumulation have been studied in an array of conditions, including hepatocellular carcinoma (4) and cardiovascular disease (5). While there have been studies examining alterations in serum lipid profiles following chronic alcohol use in mice and humans (6, 7), very few clinical studies have investigated the specific lipidomic changes that are associated with ALD. One enzymatic pathway which has been implicated in the progression of several diseases, including non-alcohol-associated fatty liver disease (8), is catalyzed by stearoyl-CoA desaturase 1 (SCD1), which increases the concentration of monounsaturated fatty acids by converting palmitic acid to palmitoleic acid and stearic acid to oleic acid. Rodent models suggest that this pathway may also be involved in ALD. For example, SCD1 knockout mice do not exhibit upregulated de novo lipogenesis in response to alcohol and are resistant to ALD (9). Targeting several regulators of SCD1 expression attenuates the deleterious impact of alcohol on the liver in animal models (10). Studies have shown that agonists of peroxisome proliferator-activated receptor gamma (11) and alpha (12), which act as inhibitory transcription factors of SCD1, help prevent alcohol-induced steatosis in ethanol-consuming rats. This is primarily through downregulation of SCD1 expression, although this relationship is dependent on tissue-specific PPAR gene regulation. Moreover, diminished SCD1 activity is a central component of the hepatoprotective effect of dietary saturated fat against alcohol-associated fatty liver disease in rodents (13, 14). Thus, the preclinical literature suggests that SCD1 activity may be implicated in the pathogenesis of ALD. However, despite this evidence, it remains unclear if SCD1 activity is associated with ALD in humans, especially in the early stage of ALD.

In order to better characterize lipidomic shifts in ALD, we examined plasma fatty acid levels in a sample of 169 AUD patients with and without ALD. Based on the preclinical literature, we hypothesized that SCD1 activity would be increased in individuals with ALD. We further employed mediation models to examine the hypothesis that chronic binge drinking induces liver disease in part by altering SCD1 activity.

MATERIALS AND METHODS

Participants and Recruitment

Individuals between the ages of 21 and 65 years were recruited under three NIAAA protocols (98-AA-0009, 05-AA-0121, 14-AA-0181) that were approved by the National Institutes of Health Institutional Review Board. As described previously (15), these protocols serve to extensively phenotype individuals across the spectrum of alcohol use as part of a comprehensive evaluation of the natural history of AUD. Participants were assessed at the National Institutes of Health (NIH) Clinical Center (CC) (Bethesda, Maryland, USA), and provided written informed consent. Urinalysis was conducted to detect recent consumption of illicit substances in all participants and for pregnancy in females. Participants were also excluded if they were less than 18 years old or unable to provide informed consent.

A total of 1082 individuals provided blood plasma samples that were assayed for fatty acid concentrations. This sample included patients admitted for inpatient detoxication and treatment in the NIAAA treatment program as well as non-treatment-seeking participants across the spectrum of alcohol consumption. Across the sample, 337 individuals reported at least one binge drinking day per week (≥4 drinks for females or ≥5 drinks for males), as assessed by the 90-day Timeline Followback (TLFB90) (16). Participants who did not have a hepatic panel performed were excluded from the analysis (n = 123). Participants who did not have alcohol consumption, hepatic panel, and fatty acid concentration measures collected within 3 days of one another were also excluded (n = 45). Following exclusion of 168 subjects on the basis of these two criteria, the final sample included 169 individuals. Participants were screened and confirmed to be negative for both Hepatitis C and HIV using an ELISA assay.

Assessments

Blood samples were obtained from patients on the morning after admission to the program, and from non-treatment-seeking participants upon arrival to the clinic for assessment. Abstention from alcohol consumption was verified using a breathalyzer. Participants were instructed to fast overnight prior to blood sampling. Concentrations of individual lipids and relevant biochemical components of lipid metabolism were measured using a clinical blood serum chemistry panel assay that used gas chromatography-mass spectrometry (GC/MS) to quantify fatty acid concentrations (17). Markers of liver function including aspartate transaminase (AST), alanine transaminase (ALT), gamma-glutamyl transferase (GGT), bilirubin, albumin levels, and platelet counts were also measured. In this study, ALT levels were used as cut-off to classify participants into non-ALD (ALT ≤40 IU/L) and ALD (>40 IU/L) groups based on the guideline set by the NIH CC Department of Laboratory Medicine (DLM) (18). Participants presented without any clinical presentation of advanced forms of ALD (such as alcohol-associated cirrhosis or hepatitis).

In addition, participants completed a 90-day Timeline Followback (TLFB) interview, a method of retrospectively estimating daily drinking using a calendar and memory aids to enhance recall (16). These interviews have been found to have high test-retest reliability (23) and are widely used as measures of alcohol consumption in clinical studies. Our analysis used the average number of binge drinking days per week over the 90-day period prior to assessment. Binge drinking cutoffs were set in accordance with the NIAAA definition of four or more drinks for women and five or more drinks for men on any given day (19). One hundred and fifty of our subjects were assessed for AUD using the Structured Clinical Interview for DSM-IV axis I disorders (SCID-IV) (20).

Analysis of Plasma Fatty Acid Levels and SCD1 Activity

Analyses of plasma fatty acid levels used the percentage of absolute individual lipid concentrations (Table 2) divided by total lipid concentration. This accounts for increases in total lipid concentration that were associated with binge drinking (Spearman’s rho = 0.153, p = 0.047). Initial analyses compared plasma fatty acid levels in individuals with and without ALD using Bonferroni-corrected Mann-Whitney tests to account for multiple comparisons and decrease the risk of Type I error (Chen et al., 2017) (27 comparisons, ɑ < 0.0018). As these analyses indicated that SCD1 activity was altered in the ALD group, we conducted additional analyses to determine whether SCD1 activity mediated the effects of binge drinking on ALT levels.

Table 2.

Percentage fatty acid group differences between non-ALD and ALD Groups.

Fatty Acid Non-ALD Group Percent (SD)
(n = 84)		 ALD Group Percent (SD)
(n = 85)		 p-value
Saturated Fatty Acids
Lauric 0.144 (0.089) 0.161 (0.094) 0.239
Myristic 1.169 (0.498) 1.325 (0.661) 0.087
Palmitic 17.276 (3.714) 17.908 (3.703) 0.269
Stearic 7.763 (1.190) 8.068 (1.222) 0.102
Arachidic 0.371 (0.130) 0.323 (0.113) 0.013
ω-3 Fatty Acids
α-Linolenic 0.758 (0.236) 0.775 (0.275) 0.672
Eicosapentaenoic 0.908 (0.477) 1.108 (0.714) 0.034
Docosapentaenoic (22:5, n-3) 0.787 (0.365) 0.894 (0.387) 0.066
Docosahexaenoic 1.746 (0.840) 1.918 (0.998) 0.225
ω-6 Fatty Acids
Linoleic 33.924 (5.880) 30.516 (6.375) < 0.001*
γ-Linolenic 0.705 (0.318) 0.738 (0.356) 0.521
homo-γ-Linolenic 1.060 (0.305) 1.073 (0.283) 0.768
Arachidonic 11.622 (3.264) 10.636 (2.480) 0.029
Docosatetaenoic 0.241 (0.084) 0.277 (0.117) 0.020
Docosapentaenoic (22:5, n-6) 0.280 (0.150) 0.271 (0.129) 0.707
ω-7 Fatty Acids
Palmitoleic 2.959 (1.427) 4.426 (1.702) < 0.001*
Vaccenic 2.999 (1.137) 3.413 (1.255) 0.026
ω-9 Fatty Acids
Hexadecenoic 0.442 (0.179) 0.465 (0.220) 0.459
Oleic 13.909 (2.851) 14.786 (3.038) 0.055
Mead 0.164 (0.064) 0.158 (0.050) 0.550
Docosenoic 0.072 (0.036) 0.066 (0.025) 0.240
Nervonic 0.692 (0.142) 0.681 (0.142) 0.608
Monounsaturated Acid 2396.0 (777) 2970.0 (928) < 0.001*
Polyunsaturated Acid 5920 (1572) 5965.5 (1538) 0.850
Total Fatty Acids 11342 (2435) 12369.3 (2603) 0.009
SCD1 Ratio 1 0.173 (0.077) 0.251 (0.099) < 0.001*
Triene/Tetraene Ratio 2 1.597 (0.977) 1.589 (0.667) 0.949
Open in a new tab
*

Threshold for significance is 0.0018 based on a Bonferroni correction to account for multiple comparisons.

To investigate whether SCD1 activity was associated with ALD, linear regression analyses were conducted, controlling for sex, BMI, and binge drinking days per week. SCD1 activity was estimated as the ratio of palmitoleic acid (16:1n7) to palmitic acid (16:0) acid. This method has been employed in lipid metabolic studies of non-alcohol-associated fatty liver disease (21, 22) and validated as an indirect marker of de novo lipogenesis (23). Furthermore, the SCD1 activity index using 16:1/16:0 has been shown to more accurately reflect SCD1 mRNA expression levels compared with that of stearic acid desaturation (18:1/18:0) (8). Values were imputed with the median for five individuals with missing height and with group medians (ALD or non-ALD) for ten individuals missing HDL cholesterol levels. Sequential regression models were used to assess whether SCD1 activity mediated the relationship between binge drinking and ALT levels as the marker of ALD (24). Sobell’s test for mediation and confidence intervals of indirect to direct effects of binge drinking on ALT based on 5000 bootstrapped samples via the SPSS Process Macro v3.0 (25) were used to assess whether SCD1 mediation was statistically significant (26).

RESULTS

Sample Characteristics

Demographics, drinking and other characteristics of the non-ALD (n = 84) and ALD (n = 85) groups are presented in Table 1. Compared to the non-ALD group, the ALD group reported a greater median number of binge drinking days per week and had lower average body-mass index (BMI) scores. There were expected differences in γ-glutamyltransferase (GGT) and aspartate transaminase (AST) levels between groups.

Table 1.

Demographics and Baseline Characteristics of Study Sample

Healthy range Non-ALD Group
(n = 84)		 ALD Group
(n = 85)		 p-value
N (%) N (%)
Female (n; %) --- 35; 41.6% 24; 28.2% 0.067
Mean (SD) Mean (SD)
Age (years) --- 41.8 (10.5) 43.9 (10.0) 0.166
BMI (kg/m2) 18.5–24.9 27.5 (5.4) 25.9 (4.0) 0.037*
HDL cholesterol (mg/dL) >60 73.1 (31.9) 81.3 (33.9) 0.117
LDL cholesterol (mg/dL) 100–130 97.8 (34.2) 107.4 (45.5) 0.132
Platelet 150–450 269.2 (75.9) 216.7 (85.1) <0.001*
Albumin (g/dL) 3.5–5.5 3.8 (0.3) 3.9 (0.4) 0.496
AST:ALT ratio <1 0.96(0.4) 1.3(0.7) <0.001*
Median (IQR) Median (IQR)
Triglycerides (mg/dL) <150 90.0 (62.0) 98.5 (98.0) 0.419
ALT (U/L) 7–55 26.0 (10.0) 87.5 (59.0) <0.001*
AST (U/L) 8–48 22.0 (11.0) 95.0 (101.0) <0.001*
GGT (U/L) 9–48 38.0 (37.0) 147.0 (276.0) <0.001*
Open in a new tab

Alcohol-associated Liver Disease (ALD); Body mass index (BMI); High-density lipoprotein (HDL) cholesterol; Low-density lipoprotein (LDL) cholesterol; Alanine transaminase (ALT); Aspartate transaminase (AST); gamma-glutamyl transferase (GGT)

Missing values: BMI (2 in non-ALD group, 3 in ALD group); Cholesterol (1 in non-ALD group, 9 in ALD group)

Mean and standard deviation reported for normally distributed data and group comparison were made using t tests; median and interquartile range reported for non-normally distributed data and group comparison were made using Mann-Whitney U test.

Fatty Acid Profile and ALD

As shown in Table 2 and Figure 1, total fatty acid concentration (U (95,74)= 2669.0, p =0.005) and monounsaturated fatty acids (U(103,66) = 1990.5, p < 0.001) were higher in the ALD group compared to the non-ALD group. Using a Bonferroni corrected alpha of 0.0018 to account for multiple comparisons, palmitoleic acid, the product of SCD1 enzymatic activity, was found to be higher in the ALD group (U(106,63)= 1763.0, p < 0.001). The measure of SCD1 activity (ratio of palmitoleic to palmitic acid) was also significantly different between groups (U(104,65)= 1939, p < 0.001). Linoleic acid, an omega-6 fatty acid, was also found to be significantly lower in the ALD group compared to controls (U(106,63)= 2482.0, p < 0.001). No statistically-significant group differences were observed, following correction for multiple comparisons, for any of the other individual fatty acids or ratios that were examined, including the plasma triene/tetraene ratio (U(89,80) = 3219.5, p = 0.267), which provides a measure of essential fatty acid intake (42).

Figure 1.

Figure 1

Open in a new tab

Change in individual fatty acid concentrations with alcohol-associated liver disease (ALD) and binge drinking correcting for increased total fatty acid content

Shaded circle indicates significant association with alcohol-associated liver disease (ALD) (using a Bonferroni corrected significance threshold) in the current study.

SCD1 Activity and ALD

We assessed whether SCD1 activity was associated with alcohol-related liver injury. SCD1 activity was significantly correlated with ALT levels (r = 0.308, p < 0.001, Figure 2). Subsequent linear regression analysis demonstrated that SCD1 was significantly associated with ALT levels (Beta = 0.260, t(167) = 3.437, p = 0.001) when controlling for binge drinking days per week (Beta = 0.210, t(167) = 2.802, p = 0.006), BMI (Beta = 0.038, t(167) = 0.518, p = 0.605), and sex (Beta = 0.111, t(167) = 1.538, p = 0.126).

Figure 2.

Figure 2

Open in a new tab

Scatter plot of SCD1 activity versus ALT levels across all participants. (r = 0.308, p < 0.001).

To determine if SCD1 activity mediated the effects of binge drinking on ALD, we performed the steps recommended by Baron and Kenny (24) (Table 3). Initial linear regression analyses found that binge drinking significantly predicted both ALT levels (Model 1; Beta = 0.278, t(167) = 3.460, p < 0.001, R2 = 0.072) and SCD1 activity (Model 2; Beta = 0.282, t(167) = 3.798, p < 0.001, R2 = 0.074). SCD1 activity also predicted ALT levels (Model 3; Beta = 0.089, t(167) = 5.775, p < 0.001, R2 = 0.089), which as mentioned previously remained significant when controlling for BMI, binge drinking and sex. We then simultaneously examined the effect of SCD1 activity and binge drinking on ALT levels. Both SCD1 activity and binge drinking days per week significantly predicted ALT levels (Model 4; binges per week: Beta = 0.208, t(166) = 2.141, p = 0.006; SCD1 activity: Beta = 0.249, t(166) = 4.996, p < 0.001; R2 = 0.124), but the effect of binge drinking days per week on ALT levels was reduced, indicating that SCD1 activity mediated the effects of binge drinking on ALD. This association was not significantly different when controlling for BMI, binge drinking and sex (Model 5; binges per week: b = 0.180, t(166) = 2.032, p = 0.009; SCD1 activity: b = 0.247, t(166) = 4.959, p < 0.001; R2 = 0.133). Sobel’s test (z = 2.986, p = 0.003) along with a bootstrapping analysis (ratio of indirect to direct effects of binge drinking on ALD = 0.658; 95% confidence interval = 0.203, 3.223) confirmed that SCD1 was a significant mediator (Figure 3).

Table 3.

Analysis of SCD1 Mediation of Alcohol-associated Liver Disease (ALD).

R2 Coefficient (95% CI) p-value
Model 1: ALT 0.072 < 0.001
Binge drinking1 0.072 0.278 (3.562, 11.511) < 0.001
Model 2: SCD1 Activity2 0.074 < 0.001
Binge drinking1 0.074 0.282 (0.759, 2.401) < 0.001
Model 3: ALT 0.089 < 0.001
SCD1 Activity2 0.089 0.308 (0.786, 2.191) < 0.001
Model 4: ALT 0.124 < 0.001
SCD1 Activity2 0.249 (0.487, 1.923) 0.001
Binge drinking1 0.208 (1.608, 9.657) 0.006
Model 5: ALT 0.133 < 0.001
SCD1 Activity2 0.247 (0.438, 1.949) 0.001
Binge drinking1 0.180 (0.667, 9.306) 0.009
Sex3 −0.097 (−24.788, 5.255) 0.271
BMI −0.859 (−2.183, 0.860) 0.121
Open in a new tab
1

Average number of binge drinking days per week over the 90-day period prior to assessment.

2

SCD1 activity was estimated by the ratio of palmitoleic acid (16:1n7) to palmitic acid (16:0) acid

3

Sex was coded as a binary variable (1 = female, 0 = male)

Figure 3.

Figure 3

Open in a new tab

Graphical and schematic representations of medication analysis of the effects of SCD1 activity on the association between binge drinking frequency and ALD.

A. Relationship between binge drinking days per week and ALT levels across levels of SCD activity. Participants were stratified into 9 groups according to terciles of SCD1 activity (low, moderate, high) and binge drinking days per week for graphical representation. Data in bar graph expressed as mean ± SEM.

B. Mediation model of SCD1 activity effects on association between binge drinking frequency and ALD.

DISCUSSION

Our study found that SCD1 activity is associated with markers of early-stage ALD in patients with alcohol use disorder, which has not been reported previously. These findings indicate that SCD1 activity may predict risk for ALD progression, as identified by ALT levels in our study. Furthermore, our models suggest that SCD1 activity may mediate the effects of binge drinking on ALT levels, which serve as an early marker of alcohol-related liver injury. This is important because despite the high level of binge alcohol consumption in our sample, only some participants displayed signs of liver injury. This finding suggests that between-subject variation in SCD1 activity may partly explain why certain individuals with AUD exhibit ALD while others do not. Additional studies are needed to reveal the molecular mechanisms underlying these associations and prospective studies should be conducted to help determine whether this association is causal before the clinical utility of these findings should be considered.

If SCD1 activity is indeed associated with the development of ALD, there may be ways to inhibit this enzyme and thereby prevent disease progression. There are currently several methods for regulating SCD1 activity, primarily through altered regulation of SCD1 expression (14,27), using nutritional supplementation with fish oil supplements (28) or dietary saturated fat (13). Specific pharmacologic inhibitors of SCD1 have also been identified, but these have yet to be either tested or approved in humans (29, 30). Currently, SCD1 inhibitors are not liver-specific, which may contribute to extra-hepatic adverse effects such as inflammation and skin and eye abnormalities seen in preclinical studies (31,32). Developing liver-specific SCD1 inhibitors may mitigate some of these concerns (35), although blocking a critical enzymatic step such as SCD1 may alter lipid homeostasis, which could have unintended consequences. These effects will have to be considered before SCD1 inhibitors can be tested in humans.

A potential limitation in our study was the extraction of total plasma lipids for GC-MS analyses. Measuring lipid concentrations from liver biopsies is a more direct method of quantifying lipidomic shifts due to binge drinking and would have provided a direct index of ALD. Using total plasma lipids for GC-MS analysis also precludes the possibility of measuring fatty acid concentrations within various lipid classes, including VLDL, triglycerides, phospholipids, cholesterol esters, and free fatty acids. This introduces additional potential bias, as it has been shown that lipids taken from certain subfractions, such as VLDL, may better correlate with hepatic lipid levels (Andres et al., 2009). Using lipid concentration values extracted from whole blood plasma also does not account for potential effects due to lipid deposits from extrahepatic sources such as the GI tract and fat deposits. However, studies show that plasma fatty acid levels can be reliable markers of changes in liver metabolism (37), particularly with regards to fatty acids that are present at low concentrations in foods. Such is the case with palmitoleic acid (40) that is often used for assessment of SCD1 activity (38). Although absolute concentration of fatty acids varies within each of these classes, similar trends across relative lipid classes were shown in a comparison of healthy controls to individuals with ALD (21, 39). In addition, individual variation in lipid profiles in response to heavy drinking has also been shown to be more sensitive among females (20), indicating that findings may be affected by sex.

Despite the requisite overnight fast for study participation, an additional potential limitation in our data was the absence of dietary intake assessment. This may be relevant given the impact of heavy drinking on diet, as studies have shown that heavy drinking is associated with lower nutrient intake (41). We also did not assess type of alcohol typically consumed (e.g. spirits, wine, or beer), which may have additional impacts on nutrient intake. These potential confounds may contribute to the secondary finding in our study of significantly diminished levels of linoleic acid, an essential fatty acid, among subjects with liver injury. However, this finding was also shown in a similar study on nonalcoholic fatty liver disease (NAFLD) and attributed to elevated delta-6 desaturase activity (21). To control for variability between subjects, we used the percentages of individual fatty acids divided by total fatty acids. We also assessed variation in the triene/tetraene ratio, which is a clinical marker of essential fatty acid deficiency (40). We found no association between triene/tetraene ratio and ALD, indicating that dietary essential fatty acid deficiency was unlikely to have been a significant contributor to our findings. Furthermore, the association of SCD1 with ALD remained significant when we controlled our analysis for BMI and sex.

This study is not able to assess a causal link between SCD1 activity and ALD given that results are only based on ALT changes and limited by the observational, cross-sectional study design. This study was also limited to early-stage of ALD, as individuals with alcohol-associated cirrhosis and alcohol-associated hepatitis were not included in our sample. Nonetheless, it is vital characterize SCD1 activity tin early stage ALD as it could be useful in predicting advanced ALD. Furthermore, despite the observed association between elevated SCD1 activity both preclinical studies of ALD (9, 11) and clinical studies of nonalcohol-associated fatty liver disease (42), the effect of SCD1 on liver disease is unclear. For example, a preclinical study found that the SCD1 product, palmitoleic acid, is protective against steatosis through stimulation of insulin signaling (43). At the same time, increased dietary consumption of palmitoleic acid and SCD1 activity are reliable markers of metabolic disorder (44) and its associated symptoms (45). This raises an evident paradox that has been previously identified (36) whereby exogenous intake of palmitoleic acid appears to be protective of liver disease whereas endogenous palmitoleic acid can have deleterious consequences. Additional preclinical studies investigating the effects of these fatty acids on hepatic function coupled with prospective studies that investigate SCD1 activity in individuals at high risk for ALD would help clarify the relation between SCD1 activity and hepatic dysfunction.

In conclusion, the findings of this study suggest that the association between SCD1 activity and ALD that has been demonstrated in preclinical models may translate to humans. Further validation of findings with a prospective cohort is warranted in order to assess whether SCD1 activity provides a marker of ALD progression and a potential target for intervention.

Supplementary Material

1

HIGHLIGHTS.

Klepp et al., Elevated Stearoyl-CoA Desaturase 1 Activity is associated with Alcohol-associated Liver Disease

  • Frequency of binge drinking was associated with alanine transaminase (ALT), a marker of alcohol-associated liver disease (ALD) in binge drinkers with and without alcohol use disorder.

  • Stearoyl-CoA Desaturase 1 (SCD-1) Activity (estimated as palmitoleic acid (16:1) to palmitic acid (16:0) ratio) was significantly elevated in individuals with alcohol-associated liver disease.

  • SCD1 activity mediated the association between binge drinking frequency and ALD.

Acknowledgements:

We are grateful to the staff of the 1-SE inpatient unit at the NIH Clinical Center as well as the clinical research staff of the NIAAA intramural clinical program for their support.

Funding:

This work was supported by the NIAAA Division of Intramural Clinical and Biological Research (Z1A AA000466, V.A.R.) and the Intramural Program of NIA (C.E.R.), and Extramural AA3 Program K23 AA029198 (V.V.).

Abbreviations:

(SCD1)

Stearoyl-CoA desaturase 1

(ALD)

alcohol-associated liver disease

(NAFLD)

nonalcoholic fatty liver disease

(GC/MS)

gas chromatography-mass spectrometry

(AST)

aspartate transaminase

(ALT)

alanine transaminase

(TLFB)

timeline follow-back

(HDD90)

number of heavy drinking days in the past 90 days

(BMI)

body-mass index

(LDL)

cholesterol low-density lipoprotein

(HDL)

cholesterol high-density lipoprotein

(VLDL)

very low density lipoprotein

Footnotes

Declaration of Interests: All authors declare no conflicts of interest.

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

References

  • 1.Walsh K, Alexander G. Alcoholic liver disease. Postgrad Med J 2000;76:280–286. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Chiung M Chen Y-HY. Trends in alcohol-related morbidity among community hospital discharges, United States, 2000–2015. Arlington, VA 22203: National Institutes of Health; 2018. [Google Scholar]
  • 3.Ceni E, Mello T, Galli A. Pathogenesis of alcoholic liver disease: role of oxidative metabolism. World J Gastroenterol 2014;20:17756–17772. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Igal RA. Stearoyl CoA desaturase-1: New insights into a central regulator of cancer metabolism. Biochim Biophys Acta 2016;1861:1865–1880. [DOI] [PubMed] [Google Scholar]
  • 5.Dobrzyn P, Bednarski T, Dobrzyn A. Metabolic reprogramming of the heart through stearoyl-CoA desaturase. Prog Lipid Res 2015;57:1–12. [DOI] [PubMed] [Google Scholar]
  • 6.Teubert A, Thome J, Buttner A, Richter J, Irmisch G. Elevated oleic acid serum concentrations in patients suffering from alcohol dependence. J Mol Psychiatry 2013;1:13. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Vatsalya V, Barve SS, McClain CJ, Ramchandani VA. Elevated Linoleic Acid (A Pro-Inflammatory PUFA) and Liver Injury in a Treatment Naive HIV-HCV Co-Infected Alcohol Dependent Patient. J Biosci Med (Irvine) 2016;4:23–27. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Hodson L, Fielding BA. Stearoyl-CoA desaturase: rogue or innocent bystander? Prog Lipid Res 2013;52:15–42. [DOI] [PubMed] [Google Scholar]
  • 9.Lounis MA, Escoula Q, Veillette C, Bergeron KF, Ntambi JM, Mounier C. SCD1 deficiency protects mice against ethanol-induced liver injury. Biochim Biophys Acta 2016;1861:1662–1670. [DOI] [PubMed] [Google Scholar]
  • 10.Hodson L, Karpe F. Is there something special about palmitoleate? Curr Opin Clin Nutr Metab Care 2013;16:225–231. [DOI] [PubMed] [Google Scholar]
  • 11.Tomita K, Azuma T, Kitamura N, Nishida J, Tamiya G, Oka A, Inokuchi S, et al. Pioglitazone prevents alcohol-induced fatty liver in rats through up-regulation of c-Met. Gastroenterology 2004;126:873–885. [DOI] [PubMed] [Google Scholar]
  • 12.Fischer M, You M, Matsumoto M, Crabb DW. Peroxisome proliferator-activated receptor alpha (PPARalpha) agonist treatment reverses PPARalpha dysfunction and abnormalities in hepatic lipid metabolism in ethanol-fed mice. J Biol Chem 2003;278:27997–28004. [DOI] [PubMed] [Google Scholar]
  • 13.You M, Cao Q, Liang X, Ajmo JM, Ness GC. Mammalian sirtuin 1 is involved in the protective action of dietary saturated fat against alcoholic fatty liver in mice. J Nutr 2008;138:497–501. [DOI] [PubMed] [Google Scholar]
  • 14.Yin H, Hu M, Zhang R, Shen Z, Flatow L, You M. MicroRNA-217 promotes ethanol-induced fat accumulation in hepatocytes by down-regulating SIRT1. J Biol Chem 2012;287:9817–9826. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Sloan ME, Klepp TD, Gowin JL, Swan JE, Sun H, Stangl BL, Ramchandani VA. The OPRM1 A118G polymorphism: converging evidence against associations with alcohol sensitivity and consumption. Neuropsychopharmacology 2018. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Sobell L, Sobell M. Timeline Followback: A Technique for Assessing Self Reported Ethanol Consumption. Vol. 17. In: Totowa, NJ: Humana Press; 1992. [Google Scholar]
  • 17.Lagerstedt SA, Hinrichs DR, Batt SM, Magera MJ, Rinaldo P, McConnell JP. Quantitative determination of plasma c8-c26 total fatty acids for the biochemical diagnosis of nutritional and metabolic disorders. Mol Genet Metab 2001;73:38–45. [DOI] [PubMed] [Google Scholar]
  • 18.Vatsalya V, Song M, Schwandt ML, Cave MC, Barve SS, George DT, Ramchandani VA. Effects of Sex, Drinking History, and Omega-3 and Omega-6 Fatty Acids Dysregulation on the Onset of Liver Injury in Very Heavy Drinking Alcohol-Dependent Patients. Alcohol Clin Exp Res 2016;40:2085–2093. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Health UDo, Services H. NIAAA council approves definition of binge drinking. NIAAA newsletter; 2004;3. [Google Scholar]
  • 20.First MB SR, Gibbon M, Williams JB. Structured clinical interview for DSM-IV-TR axis I disorders, Research Version, Patient Edition. 2002.
  • 21.Puri P, Wiest MM, Cheung O, Mirshahi F, Sargeant C, Min HK, Contos MJ, et al. The plasma lipidomic signature of nonalcoholic steatohepatitis. Hepatology 2009;50:1827–1838. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Muir K, Hazim A, He Y, Peyressatre M, Kim DY, Song X, Beretta L. Proteomic and lipidomic signatures of lipid metabolism in NASH-associated hepatocellular carcinoma. Cancer Res 2013;73:4722–4731. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Jump DB, Botolin D, Wang Y, Xu J, Christian B, Demeure O. Fatty acid regulation of hepatic gene transcription. J Nutr 2005;135:2503–2506. [DOI] [PubMed] [Google Scholar]
  • 24.Baron RM, Kenny DA. The moderator-mediator variable distinction in social psychological research: conceptual, strategic, and statistical considerations. J Pers Soc Psychol 1986;51:1173–1182. [DOI] [PubMed] [Google Scholar]
  • 25.Hayes AF. Introduction to mediation, moderation, and conditional process analysis: A regression-based approach: Guilford Press, 2013. [Google Scholar]
  • 26.Preacher KJ, Kelley K. Effect size measures for mediation models: quantitative strategies for communicating indirect effects. Psychol Methods 2011;16:93–115. [DOI] [PubMed] [Google Scholar]
  • 27.Mauvoisin D, Mounier C. Hormonal and nutritional regulation of SCD1 gene expression. Biochimie 2011;93:78–86. [DOI] [PubMed] [Google Scholar]
  • 28.Wada S, Yamazaki T, Kawano Y, Miura S, Ezaki O. Fish oil fed prior to ethanol administration prevents acute ethanol-induced fatty liver in mice. J Hepatol 2008;49:441–450. [DOI] [PubMed] [Google Scholar]
  • 29.Uto Y, Ueno Y, Kiyotsuka Y, Miyazawa Y, Kurata H, Ogata T, Takagi T, et al. Discovery of novel SCD1 inhibitors: 5-alkyl-4,5-dihydro-3H-spiro[1,5-benzoxazepine-2,4’-piperidine] analogs. Eur J Med Chem 2011;46:1892–1896. [DOI] [PubMed] [Google Scholar]
  • 30.Shi Y, Burn P. Lipid metabolic enzymes: emerging drug targets for the treatment of obesity. Nat Rev Drug Discov 2004;3:695–710. [DOI] [PubMed] [Google Scholar]
  • 31.Miyazaki M, Man WC, Ntambi JM. Targeted disruption of stearoyl-CoA desaturase1 gene in mice causes atrophy of sebaceous and meibomian glands and depletion of wax esters in the eyelid. J Nutr 2001;131:2260–2268. [DOI] [PubMed] [Google Scholar]
  • 32.Sampath H, Ntambi JM. Role of stearoyl-CoA desaturase-1 in skin integrity and whole body energy balance. J Biol Chem 2014;289:2482–2488. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Brown JM, Rudel LL. Stearoyl-coenzyme A desaturase 1 inhibition and the metabolic syndrome: considerations for future drug discovery. Curr Opin Lipidol 2010;21:192–197. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Miyazaki M, Kim YC, Ntambi JM. A lipogenic diet in mice with a disruption of the stearoyl-CoA desaturase 1 gene reveals a stringent requirement of endogenous monounsaturated fatty acids for triglyceride synthesis. J Lipid Res 2001;42:1018–1024. [PubMed] [Google Scholar]
  • 35.Oballa RM, Belair L, Black WC, Bleasby K, Chan CC, Desroches C, Du X, et al. Development of a liver-targeted stearoyl-CoA desaturase (SCD) inhibitor (MK-8245) to establish a therapeutic window for the treatment of diabetes and dyslipidemia. J Med Chem 2011;54:5082–5096. [DOI] [PubMed] [Google Scholar]
  • 36.Liu J, Cinar R, Xiong K, Godlewski G, Jourdan T, Lin Y, Ntambi JM, et al. Monounsaturated fatty acids generated via stearoyl CoA desaturase-1 are endogenous inhibitors of fatty acid amide hydrolase. Proc Natl Acad Sci U S A 2013;110:18832–18837. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Lee JJ, Lambert JE, Hovhannisyan Y, Ramos-Roman MA, Trombold JR, Wagner DA, Parks EJ. Palmitoleic acid is elevated in fatty liver disease and reflects hepatic lipogenesis. Am J Clin Nutr 2015;101:34–43. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Peter A, Cegan A, Wagner S, Lehmann R, Stefan N, Konigsrainer A, Konigsrainer I, et al. Hepatic lipid composition and stearoyl-coenzyme A desaturase 1 mRNA expression can be estimated from plasma VLDL fatty acid ratios. Clin Chem 2009;55:2113–2120. [DOI] [PubMed] [Google Scholar]
  • 39.Puri P, Baillie RA, Wiest MM, Mirshahi F, Choudhury J, Cheung O, Sargeant C, et al. A lipidomic analysis of nonalcoholic fatty liver disease. Hepatology 2007;46:1081–1090. [DOI] [PubMed] [Google Scholar]
  • 40.Sardesai VM. The essential fatty acids. Nutr Clin Pract 1992;7:179–186. [DOI] [PubMed] [Google Scholar]
  • 41.Ma J, Betts NM, Hampl JS. Clustering of lifestyle behaviors: the relationship between cigarette smoking, alcohol consumption, and dietary intake. Am J Health Promot. 2000. Nov–Dec;15(2):107–17. doi: 10.4278/0890-1171-15.2.107. [DOI] [PubMed] [Google Scholar]
  • 42.Maciejewska D, Drozd A, Ossowski P, Ryterska K, Jamiol-Milc D, Banaszczak M, Raszeja-Wyszomirska J, et al. Fatty acid changes help to better understand regression of nonalcoholic fatty liver disease. World J Gastroenterol 2015;21:301–310. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43.Cao H, Gerhold K, Mayers JR, Wiest MM, Watkins SM, Hotamisligil GS. Identification of a lipokine, a lipid hormone linking adipose tissue to systemic metabolism. Cell 2008;134:933–944. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44.Warensjo E, Riserus U, Vessby B. Fatty acid composition of serum lipids predicts the development of the metabolic syndrome in men. Diabetologia 2005;48:1999–2005. [DOI] [PubMed] [Google Scholar]
  • 45.Paillard F, Catheline D, Duff FL, Bouriel M, Deugnier Y, Pouchard M, Daubert JC, et al. Plasma palmitoleic acid, a product of stearoyl-coA desaturase activity, is an independent marker of triglyceridemia and abdominal adiposity. Nutr Metab Cardiovasc Dis 2008;18:436–440. [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

1
NIHMS1801186-supplement-1.pdf (212.1KB, pdf)

RESOURCES