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. 2025 Jul 28;26(15):7304. doi: 10.3390/ijms26157304

Fatty Acid Profile in the Liver of Mice with Early- and Late-Onset Forms of Huntington’s Disease

Magdalena Gregorczyk 1, Adriana Mika 2,3, Tomasz Śledziński 3, Marta Tomczyk 4, Iwona Rybakowska 1,*
Editor: Elena Vianello
PMCID: PMC12347809  PMID: 40806436

Abstract

Huntington’s disease (HD) is characterized by progressive neurodegeneration, but increasing evidence points to multisystemic involvement, including early hepatic steatosis in pediatric HD. Therefore, it is important to consider systemic alterations, particularly in liver lipid metabolism. In this study, we analyzed fatty acid (FA) profiles in two symptomatic HD mouse models: 2-month-old R6/2 mice representing early-onset HD and 22-month-old HdhQ150/Q150 (Hdh) mice representing late-onset HD, along with age-matched wild-type (WT) controls. FA composition in liver tissue was assessed by gas chromatography–mass spectrometry (GC–MS). In R6/2 mice, we observed increased levels of total iso-branched chain, monounsaturated, and n-6 polyunsaturated FAs compared to WT. In contrast, only a few FA species showed reduced concentrations in Hdh mice. Overall, our results indicate that R6/2 mice exhibit more pronounced alterations in hepatic FA profiles than Hdh mice, suggesting that early-onset HD may be associated with more severe peripheral metabolic dysregulation.

Keywords: Huntington’s disease, liver, fatty acids, IL1-α

1. Introduction

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder whose phenotype includes chorea movements, incoordination, behavioral disturbances, and psychiatric symptoms [1,2,3]. HD is caused by a CAG trinucleotide expansion in the huntingtin (HTT) gene, resulting in the formation of a variable-length polyglutamine strand at the N-terminus [1]. The average age of onset of the disease is around 40 years, but there are also juvenile forms that manifest before the age of 20 (5–10% of cases) and late onset of the disease after the age of 50 (20%). Unaffected individuals have a range of 6–35 CAG repeats in the HTT gene, while individuals with HD have 36–121 CAG repeats [4]. With more than 80 CAG repeats in the HTT gene, the disease appears in the first year of life [5,6]. The presence of normally functioning individuals aged 75–90 years with CAG expansions in the 36–39 range suggests that some people with small HD expansions can survive into old age without symptoms [7]. Pediatric HD contributes to an atypical, disabling, and life-shortening phenotype compared to adult HD [5]. In adult HD, the greatest CAG expansion is observed in the striatum and cerebral cortex [6]. In humans with HD, the liver exhibited the highest level of CAG expansion among the periphery tissues [8]. However, postmortem histologic examinations of the liver of adult HD patients have not revealed any morphologic changes. Changes are observed in childhood HD, where an increase in liver volume and steatosis are noted [6]. It, therefore, seems important to compare the metabolic changes that occur in early- and late-onset HD at the molecular level.

Lipid membranes might contribute to the spontaneous appearance of mHTT aggregates in the brain of R6/2 mice [9], and likely the same situation occurs in the liver. The global genomic organization and gene expression are similar between humans and mice. Like humans, mice have basic neural circuits and types of neuronal cells that are selectively affected in HD along with a rich behavioral repertoire associated with specific neuronal dysfunction and degeneration [10,11]. The liver is an important site of systemic energy metabolism, and the numerous metabolic pathways are regulated in this tissue hormonally and neuronally as well as by nutritional status [12]. Mitochondrial dysfunction is observed in the liver of HD patients [13,14], which can alter lipid metabolism and other metabolic pathways. Fatty acids (FAs) play an important role in the body: they have structural functions as components of phospholipids that build cell membranes, they serve as storage materials in cells, and their derivatives are involved in cell signaling [15]. Steatosis is an excessive ectopic accumulation of lipids in the liver that causes lipotoxicity and leads to harmful metabolic consequences such as endoplasmic reticulum stress and inflammation [16,17,18,19]. Linoleic acid (LA, 18:2n-6) is a precursor of gamma-linolenic acid (GLA, 18:3n-6), dihomo-gamma-linolenic acid (DGLA, 20:3n-6), and arachidonic acid (ARA, 20:4n-6) [20]. ARA is a precursor of several potent pro-inflammatory messengers, including well-described prostaglandins and leukotrienes [21]. HD is associated with increased inflammation, as evidenced by elevated levels of circulating proinflammatory interleukins [22]. Together with HD-associated hepatic steatosis, this may indicate increased inflammation in the liver [23]. However, the relationship between HD and liver inflammation and FA composition has not yet been investigated.

The pathological mechanisms of HD are still being investigated, and research on transgenic mice is making it possible to discover the molecular mechanisms of disease progression. Considering the occurrence of hepatic steatosis in the course of early-onset HD, and the fact that FA are substrates for the synthesis of various compounds with pro-inflammatory and anti-inflammatory properties, in the present study, we investigated FA composition and levels in the liver of two HD mouse models, R6/2 and HdhQ150/Q150 (Hdh), representing the early and late onset of HD, respectively.

2. Results

2.1. Lipid Concentration in the Liver

Although there was a trend towards higher lipid content in R6/2 mice compared to their wild-type (WT) controls, there were no statistical differences in total lipid concentration in the livers of R6/2 and HdhQ150/Q150 mice and their corresponding WT controls (Figure 1).

Figure 1.

Figure 1

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Lipid concentration in the liver of mice with Huntington’s disease R6/2 and HdhQ150/Q150 compared to WT mice of the corresponding age (WTR6/2—wild type for R6/2; WTHdh—wild type for HdhQ150/Q150). Data presented as mean ± SEM.

2.2. Fatty Acid Composition in the Liver

Among the FAs analyzed with a length between 12–30 carbon atoms (saturated, monounsaturated, and polyunsaturated), significantly more differences in their profile were observed in R6/2 mice, an early-onset form of the disease. Higher levels of iso16:0, iso17:0, 18:1, 19:1, 20:1, 20:4n-3 (ETA), 20:5n-3 (EPA), 18:2n-6 (LA), 20:2n-6 (EDA), 20:3n-6 (DGLA), 20:4n-6 (ARA), and 22:4n-6 (AdA) were found in the liver of R6/2 mice compared to WT (Table 1). Overall, the content of iso-branched-chain FA (isoBCFA), monounsaturated FA (MUFA), and n-6 polyunsaturated fatty acids (n-6 PUFA) was higher in the livers of R6/2 mice than in those of WT (Table 1, Figure 2a,b).

Table 1.

Fatty acid concentration (µg/g of tissue) in R6/2 and WT mice liver.

LIVER FAs
WT R6/2 R6/2 p
iso 14:0 0.002 ± 0.003 0.003 ± 0.004 NS
iso 15:0 0.006 ± 0.005 0.009 ± 0.002 NS
iso 16:0 0.017 ± 0.008 0.034 ± 0.010 <0.05
iso 17:0 0.023 ± 0.010 0.042 ± 0.008 <0.01
Total iso BCFA 0.048 ± 0.023 0.088 ± 0.012 <0.01
anteiso 15:0 0.011 ± 0.012 0.007 ± 0.004 NS
anteiso 17:0 0.009 ± 0.006 0.013 ± 0.003 NS
anteiso 19:0 0.022 ± 0.009 0.045 ± 0.012 <0.05
Total anteiso BCFA 0.042 ± 0.027 0.065 ± 0.012 NS
Total BCFA 0.090 ± 0.048 0.154 ± 0.019 <0.05
16:0 11.5 ± 4.17 17.0 ± 4.85 NS
18:0 4.65 ± 0.99 9.96 ± 3.53 <0.05
Other ECFA 0.49 ± 0.27 0.58 ± 0.16 NS
Total ECFA 16.6 ± 5.19 27.5 ± 8.44 NS
Total OCFA 0.25 ± 0.11 0.42 ± 0.13 NS
14:1 0.008 ± 0.008 0.011 ± 0.005 NS
16:1 1.46 ± 0.96 2.01 ± 0.40 NS
18:1 10.5 ± 6.75 25.0 ± 6.67 <0.05
19:1 0.012 ± 0.006 0.035 ± 0.014 <0.05
20:1 0.20 ± 0.12 0.54 ± 0.11 <0.05
22:1 0.024 ± 0.007 0.026 ± 0.009 NS
24:1 0.053 ± 0.017 0.097 ± 0.038 NS
Total MUFA 12.3 ± 7.85 27.7 ± 7.18 <0.05
18:3n-3 0.062 ± 0.021 0.072 ± 0.022 NS
20:4n-3 0.020 ± 0.009 0.066 ± 0.008 <0.01
20:5n-3 0.28 ± 0.10 0.61 ± 0.20 <0.05
22:5n-3 0.32 ± 0.11 0.44 ± 0.18 NS
22:6n-3 3.36 ± 0.77 5.19 ± 1.90 NS
Total PUFAn-3 4.05 ± 1.00 6.37 ± 2.25 NS
16:2n-6 0.014 ± 0.008 0.017 ± 0.05 NS
18:2n-6 8.89 ± 3.00 14.60 ± 3.61 <0.05
20:2n-6 0.16 ± 0.064 0.30 ± 0.057 <0.01
20:3n-6 0.57 ± 0.19 0.86 ± 0.18 <0.05
20:4n-6 3.68 ± 0.79 6.23 ± 1.66 <0.05
22:4n-6 0.093 ± 0.027 0.164 ± 0.050 <0.05
22:5n-6 0.028 ± 0.016 0.047 ± 0.013 NS
Total PUFAn-6 13.6 ± 4.07 22.5 ± 5.39 <0.05
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p from t-test; values are mean ± SD; NS—nonsignificant; BCFA—branched-chain fatty acids, MUFA—monounsaturated fatty acids, PUFA—polyunsaturated fatty acids, 18:3n-3—ALA; 20:4n-3—ETA; 20:5n-3—EPA; 22:5n-3—DPA n-3; 22:6n-3—DHA; 16:2n-6—HDA; 18:2n-6—LA; 20:2n-6—EDA; 20:3n-6—DGLA; 20:4n-6—ARA; 22:4n-6—AdA; 22:5n-6—DPA n-6.

Figure 2.

Figure 2

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Total concentrations of FA groups: iso BCFA, BCFA, ECFA, OCFA, MUFA, PUFAn-3, and PUFAn-6 in liver of (a) WTR6/2, (b) R6/2, (c) WTHdh, and (d) HdhQ150/Q150 mice.

Of the FAs tested in the livers of HdhQ150/Q150 mice, only the levels of EPA, 22:5n-3 (DPA), and AdA were decreased in HdhQ150/Q150 mice compared to WT (Table 2, Figure 2c,d). This suggests different mechanisms of regulation of FA metabolism in R6/2 and HdhQ150/Q150 mice with early and late disease onset, respectively.

Table 2.

Fatty acid concentration (µg/g of tissue) in HdhQ150/Q150 and WT mice liver.

LIVER FAs
WT Hdh HdhQ150/Q150 p
iso 14:0 0.009 ± 0.007 0.004 ± 0.003 NS
iso 15:0 0.012 ± 0.14 0.008 ± 0.005 NS
iso 16:0 0.04 ± 0.025 0.046 ± 0.030 NS
iso 17:0 0.045 ± 0.021 0.038 ± 0.012 NS
Total isoBCFA 0.11 ± 0.06 0.096 ± 0.041 NS
anteiso 15:0 0.024 ± 0.019 0.011 ± 0.004 NS
anteiso 17:0 0.025 ± 0.012 0.014 ± 0.01 NS
anteiso 19:0 0.064 ± 0.03 0.081 ± 0.100 NS
Total anteiso BCFA 0.11 ± 0.06 0.11 ± 0.11 NS
Total BCFA 0.22 ± 0.11 0.20 ± 0.16 NS
16:0 29.1 ± 12.9 21.5 ± 6.24 NS
18:0 12.5 ± 5.14 7.86 ± 0.74 NS
Other ECFA 0.87 ± 0.50 0.99 ± 0.64 NS
Total ECFA 42.5 ± 18.4 30.4 ± 6.95 NS
Total OCFA 0.67 ± 0.30 0.50 ± 0.14 NS
14:1 0.031 ± 0.037 0.015 ± 0.005 NS
16:1 2.62 ± 1.43 2.66 ± 2.08 NS
18:1 26.4 ± 14.4 24.7 ± 23.2 NS
19:1 0.021 ± 0.010 0.021 ± 0.024 NS
20:1 0.37 ± 0.18 0.71 ± 0.79 NS
22:1 0.032 ± 0.018 0.035 ± 0.009 NS
24:1 0.11 ± 0.036 0.07 ± 0.01 NS
Total MUFA 29.6 ± 15.9 28.2 ± 26.0 NS
18:3n-3 0.20 ± 0.09 0.10 ± 0.07 NS
20:4n-3 0.06 ± 0.05 0.03 ± 0.008 NS
20:5n-3 0.79 ± 0.32 0.38 ± 0.14 <0.05
22:5n-3 0.96 ± 0.40 0.44 ± 0.15 <0.05
22:6n-3 8.47 ± 3.45 5.08 ± 1.82 NS
Total PUFAn-3 10.5 ± 4.20 6.03 ± 2.14 NS
16:2n-6 0.04 ± 0.032 0.04 ± 0.025 NS
18:2n-6 24.2 ± 10.8 20.9 ± 13.1 NS
20:2n-6 0.39 ± 0.15 0.30 ± 0.10 NS
20:3n-6 1.01 ± 0.42 0.79 ± 0.21 NS
20:4n-6 8.31 ± 3.52 5.63 ± 1.79 NS
22:4n-6 0.30 ± 0.11 0.16 ± 0.02 <0.05
22:5n-6 0.060 ± 0.029 0.040 ± 0.011 NS
Total PUFAn-6 34.7 ± 14.4 28.1 ± 11.5 NS
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p from t-test; values are mean ± SD; NS—nonsignificant; BCFA—branched-chain fatty acids, MUFA—monounsaturated fatty acids, PUFA—polyunsaturated fatty acids, 18:3n-3—ALA; 20:4n-3—ETA; 20:5n-3—EPA; 22:5n-3—DPA n-3; 22:6n-3—DHA; 16:2n-6—HDA; 18:2n-6—LA; 20:2n-6—EDA; 20:3n-6—DGLA; 20:4n-6—ARA; 22:4n-6—AdA; 22:5n-6—DPA n-6.

2.3. IL-1α Level in the Liver

To assess inflammation, the IL-1α level was measured (Figure 3). IL-1α level increased in R6/2 mice and decreased in HdhQ150/Q150 mice, indicating different regulation of the inflammatory process in early- and late-onset HD.

Figure 3.

Figure 3

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Level of IL-1α in the liver of Huntington’s disease mouse models. R6/2 and HdhQ150/Q150 mouse models were compared to the WT mice (WTR6/2-wild type for R6/2 and WTHdh-wild type for HdhQ150/Q150). Data presented as mean ± SEM; * p < 0.05.

3. Discussion

Although HD primarily affects the brain, increasing evidence points to systemic metabolic alterations, including those occurring in the liver. Our previous studies have demonstrated that metabolic dysregulation in HD extends beyond the central nervous system, impacting peripheral organs such as the heart and skeletal muscles [24,25,26,27]. In the mouse model of Huntington’s disease BACHD presenting slow progression of the disease, which carries the full-length human HTT gene, increased levels of inflammatory cytokines IL-12p70 and TNFα were found in the liver [28]. R6/2 and HdhQ150 mice are more susceptible than WT mice to lipopolysaccharide-evoked systemic inflammation and produced more proinflammatory cytokines in the brain [29].

In this study we highlighted a significant change in the FA profile in the livers of mice with early-onset HD (R6/2), which may be associated with the development of hepatic steatosis and liver inflammation. In contrast, few changes in FA levels were found in HdhQ150/Q150 mice with late-onset HD compared to WT. The lipid content in R6/2 tended to be increased compared to WT, but this trend was not significant. This could indicate the early stage of development of liver steatosis but does not fully reflect the changes observed in early-onset HD in humans. Nonetheless, this trend could partially explain the fact that some FAs whose levels were significantly altered in R6/2 mice were elevated. Another finding suggesting an early stage in the development of hepatic steatosis is a significant increase in 18:1, a major component of TAG [30]. In the HdhQ150/Q150 mice, there were no significant changes in either total liver lipids or 18:1.

There are very few data on the association of FA metabolism with HD. However, there is evidence that mutant huntingtin (mHTT) affects SREBPs and thus may limit de novo cholesterol and FA synthesis in the brain [31]. However, our results from the liver do not indicate a limitation of de novo SFA or MUFA synthesis because some representatives of these FA groups are present in higher amounts in the liver of R6/2 mice compared to WT. We can only speculate that some brain–liver axis may be responsible for the FA alterations in the liver. It has been shown that mutation in the gene encoding huntingtin leads to increased formation of membrane structures within cells [32,33]. The increased formation of membrane structures within cells may partially contribute to the elevated levels of certain FAs observed in the livers of mice expressing the mHTT. While some differences in hepatic FA profiles were noted between the R6/2 and HdhQ150/Q150 strains—one of which reached statistical significance—these variations are likely influenced by the distinct genetic modifications underlying each HD model. To our knowledge, the relationship between these specific genetic backgrounds and liver FA composition has not been previously explored, and the current study offers an initial step toward addressing this gap.

Studies indicate the influence of mHTT expression on immune activation in the brain, which plays a role in the pathogenesis of HD [22,23]. Elevated plasma levels of IL-4, IL-5, IL-6, IL-8, and IL-10 have been observed in patients with HD [22,34,35]. IL-1β level was increased in the serum of R6/2 mice, which have an early onset of disease corresponding to the early onset of disease in humans, and did not change in HdhQ150/Q150 mice, which have a late onset of disease, compared to WT [36]. IL-6 levels were also elevated in the serum of R6/2 mice, but also in HdhQ150/Q150 mice [36]. There is a relationship between inflammatory factors such as prostaglandin E2 through stimulation with TNFα and IL-1α in astrocytes this may be caused by conversion of ARA to prostaglandin E2 [37]. There are also findings showing increased TNF-α, IL-1β in the liver, cortex, striatum, and serum of Hdh mice and TNF-α in the liver, cortex, and serum of R6/2 mice [29]. TNF-α concentration increased twofold in the liver of R6/2 mice [29], as in our research IL-1α. IL-1α may also be specific for triggering pro-inflammatory changes in the liver. Inflammation associated with hepatic steatosis, liver injury, and hepatocyte regeneration can lead to fibrosis, cirrhosis, and even hepatocellular carcinoma [38]. The presence and metabolism of PUFAs and the synthesis of PUFA-derived lipid mediators are associated with inflammation [39]. Currently, n-3 PUFAs are thought to have anti-inflammatory properties, but some n-6 PUFAs such as DGLA and AdA are also associated with an anti-inflammatory response [40]. In contrast, ARA is a precursor of proinflammatory mediators [40]. We found elevated levels of ARA as well as total n-6 PUFA in R6/2 mice, suggesting a proinflammatory FA profile. Liver inflammation might also be confirmed by elevated liver levels of IL-1α in R6/2 mice. The potential mechanism of how changes in FA profiles in the liver may contribute to inflammation is presented in Figure 4.

Figure 4.

Figure 4

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Potential mechanism of changes in FA profile on the inflammatory process in liver of R6/2 mice; mHtt- mutant huntingtin, ↑—higher amount.

The levels of ARA and PUFA did not change significantly in HdhQ150/Q150 mice, while IL1α levels were decreased. The total amount of n-6 PUFA showed a decreasing trend in HdhQ150/Q150 mice with a significantly decreased concentration of AdA. In contrast, the concentrations of anti-inflammatory n-3 PUFA did not change significantly in both R6/2 and HdhQ150/Q150 mice. Of note is the increase in total iso-BCFA in the liver of R6/2 mice. An approximately twofold increase in concentration was observed in iso16:0 and iso17:0 compared to WT. Considering that iso-BCFA has an anti-inflammatory effect in liver cells [41], it seems that the change in the concentration of iso-BCFA is related to the activation of a compensatory mechanism in the liver of R6/2 mice that protects against inflammation but may not have been effective due to the low concentrations of iso-BCFA. In the liver of HdhQ150/Q150 mice, we found a decreasing trend of iso-BCFAs except for iso-16:0, where an increasing trend was observed. The Supplementary Table S1 presents comparison of FA levels in liver between the R6/2 and Hdh mice. There are a few differences (only one significant, for ETA) probably resulting from different genetic modifications of these two models of HD (Supplementary Materials).

The limitation of this study is a lack of the analysis of mutated HTT gene expression in the liver. However, due to the fact that HTT gene expression was confirmed in the liver of mice [42] and that the presence of the mHTT gene was the only variable that distinguished our HD mice from controls, we believe that the differences in FA levels observed in the liver of R6/2 mice are the effect of HD.

In conclusion, our study demonstrates that metabolic alterations, including changes in FA composition, are markedly more pronounced in the livers of mice with early-onset HD compared to those with late-onset. These findings suggest a potential link between the altered hepatic FA profile and the development of liver inflammation. Nonetheless, further comprehensive investigations are warranted to elucidate the mechanistic basis and pathophysiological significance of these findings.

4. Materials and Methods

4.1. Animal Models

Two mouse models of HD at the symptomatic stage were used in this study: 2-month-old R6/2 mice and 22-month-old HdhQ150/Q150 mice. The R6/2 mice carry a transgene containing the 5′ fragment of the human HTT gene encoding the N-terminus of huntingtin with approximately 150 CAG repeats. They are characterized by an early onset of neurological symptoms (around 6–8 weeks of age) and rapid disease progression, with the end-stage reached by 12–14 weeks [43]. The HdhQ150/Q150 mice have approximately 150 CAG repeats knocked into the mouse Htt gene and exhibit late-onset, slowly progressing symptoms that more closely mimic the human disease. These mouse strains typically begin to show behavioral and molecular abnormalities from 12 to 18 months of age, with significant progression by 22–24 months, depending on CAG repeat length and genetic background [44].

These two mouse strains allow for the assessment of metabolic alterations associated with early- and late-onset forms of Huntington’s disease [43,44]. Wild-type (WT) mice of the C57BL/6 strain were used as controls. The experimental groups consisted of 6 WT mice and 5 mice in each of the R6/2 and HdhQ150/Q150 groups.

Animals were housed in polycarbonate cages under controlled environmental conditions: a 12:12 h light/dark cycle (lights on at 06:00), constant temperature (22 °C), relative humidity of 50–55%, and ad libitum access to standard pellet food and water.

All procedures were conducted under a project license from the Home Office, UK, and approved by the ethical committee at Imperial College London and the Medical University of Gdansk Ethics Committee for Animal Experiments.

4.2. Analysis of the Fatty Acids

The first step of FA determination was the extraction of total lipids according to the Folch method [45] with a 2:1 (v/v) chloroform-methanol mixture and subsequent hydrolysis of the lipids with KOH in methanol. Total lipids were quantified by weighting lipids extracted by the Folch method. To obtain FA methyl esters (FAMEs), a 10% boron trifluoride-methanol solution was used. Free FAs are also present in lipid samples extracted by the Folch method, and they are derivatized to FAME in the same way as FAs released from complex lipids by hydrolysis. FAMEs were analyzed by gas chromatography–mass spectrometry (GC-MS) QP-2020 NX (Shimadzu, Shimadzu Corporation, Kyoto, Japan) [46]. FAs were identified by manual integration using FA reference standards (Larodan, Solna, Sweden, and Sigma-Aldrich, Schnelldorf, Germany). The results are presented as a mg/g of wet tissue. Individual FA content was calculated based on the peak areas of individual FA and internal standard (19-methylarachidic acid).

4.3. Determination of IL-1α Level

IL-1α concentration was measured in the liver using a commercially available ELISA kit according to instructions (catalog number A76782; Antibodies, St. Louis, MO, USA). The ELISA kit was a sandwich enzyme immunoassay for the quantitative measurement of IL-1α in tissue homogenates. Tissue was homogenized in PBS (1:9). The results were read against the prepared standard curve by spectrophotometry at a wavelength of 450 nm.

4.4. Statistical Analysis

The significance of the differences was tested using the Student t-test. The differences were considered significant at p < 0.05. The results are given as mean ± standard deviation. Statistical calculations were performed using the programs Excel and SigmaPlot 11 (Systat Software, San Jose, CA, USA).

Acknowledgments

We sincerely thank Michał Mielcarek, Department of Life Sciences, Imperial College London, London, UK, for kindly providing animal tissue samples used in this study.

Supplementary Materials

The following supporting information can be downloaded at https://www.mdpi.com/article/10.3390/ijms26157304/s1.

ijms-26-07304-s001.zip (87.6KB, zip)

Author Contributions

Conceptualization, I.R., A.M., and T.Ś.; methodology, M.G., A.M., T.Ś., M.T., and I.R.; software, A.M. and I.R.; validation, I.R. and A.M.; formal analysis, I.R. and A.M.; investigation, M.G., A.M., and M.T.; resources, I.R., A.M., and T.Ś.; data curation, A.M., T.Ś., and I.R.; writing—original draft preparation, I.R.; writing—review and editing, A.M., T.Ś., and M.T.; visualization, I.R.; supervision, A.M., T.Ś., and I.R.; project administration, I.R.; funding acquisition, A.M., T.Ś., and I.R. All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement

All procedures were conducted under a project license from the Home Office, UK, and approved by the ethical committee at Imperial College London and the Medical University of Gdansk Ethics Committee for Animal Experiments. The experiments were carried out on tissues of dead animals killed humanely, for which approval is not required under Polish law.

Informed Consent Statement

Not applicable.

Data Availability Statement

The datasets and materials used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Conflicts of Interest

The authors declare no conflicts of interest.

Funding Statement

This work was supported by the Medical University of Gdansk, ST-534 (grant no. 01-30024/0006086/01/304/304/0/2024), ST-40 and IDUB project 61-00206/K21/MPK 664.

Footnotes

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References

  • 1.Walker F.O. Huntington’s disease. Lancet. 2007;369:218–228. doi: 10.1016/S0140-6736(07)60111-1. [DOI] [PubMed] [Google Scholar]
  • 2.Chang K.-H., Cheng M.-L., Lo C.-J., Fan C.-M., Wu Y.-R., Chen C.-M. Alterations of Lipoprotein Profiles in the Plasma as Biomarkers of Huntington’s Disease. Cells. 2023;12:385. doi: 10.3390/cells12030385. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Kim A., Lalonde K., Truesdell A., Welter P.C., Brocardo P.S., Rosenstock T.R., Gil-Mohapel J. New Avenues for the Treatment of Huntington’s Disease. Int. J. Mol. Sci. 2021;22:8363. doi: 10.3390/ijms22168363. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Brinkman R.R., Mezei M.M., Theilmann J., Almqvist E., Hayden M.R. The Likelihood of Being Affected with Huntington Disease by a Particular Age, for Specific CAG Size. Am. J. Hum. Genet. 1997;60:1202–1210. [PMC free article] [PubMed] [Google Scholar]
  • 5.Fusilli C., Migliore S., Mazza T., Consoli F., De Luca A., Barbagallo G., Ciammola A., Gatto E.M., Cesarini M., Etcheverry J.L., et al. Biological and clinical manifestations of juvenile Huntington’s disease a retrospective analysis. Lancet Neurol. 2018;17:986–993. doi: 10.1016/S1474-4422(18)30294-1. [DOI] [PubMed] [Google Scholar]
  • 6.Squitieri F., Monti L., Graziola F., Colafati G.S., Sabatini U. Early liver steatosis in children with pediatric Huntington disease and highly expanded CAG mutations. Park. Relat. Disord. 2022;103:102–104. doi: 10.1016/j.parkreldis.2022.08.027. [DOI] [PubMed] [Google Scholar]
  • 7.Rubinsztein D.C., Leggo J., Coles R., Almqvist E., Biancalana V., Cassiman J.-J., Chotai K., Connarty M., Craufurd D., Curtis A., et al. Phenotypic Characterization of Individuals with 30-40 CAG Repeats in the Huntington Disease (HD) Gene Reveals HD Cases with 36 Repeats and Apparently Normal Elderly Individuals with 36-39 Repeats. Am. J. Hum. Genet. 1996;59:16–22. [PMC free article] [PubMed] [Google Scholar]
  • 8.Pinto R.M., Arning L., Giordano J.V., Razghandi P., Andrew M.A., Gillis T., Correia K., Mysore J.S., Grote Urtubey D.-M., Parwez C.R., et al. Patterns of CAG repeat instability in the central nervous system and periphery in Huntington’s disease and in spinocerebellar ataxia type 1. Hum. Mol. Genet. 2020;29:2551–2567. doi: 10.1093/hmg/ddaa139. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Suopanki J., Götz C., Lutsch G., Schiller J., Harjes P., Herrmann A., Wanker E.E. Interaction of huntingtin fragments with brain membranes—Clues to early dysfunction in Huntington’s disease. J. Neurochem. 2006;96:870–884. doi: 10.1111/j.1471-4159.2005.03620.x. [DOI] [PubMed] [Google Scholar]
  • 10.Monaco G., Van Dam S., Ribeiro J.L.C.N., Larbi A., De Magalhães J.P. A comparison of human and mouse gene co-expression networks reveals conservation and divergence at the tissue, pathway and disease levels. BMC Evol. Biol. 2015;15:259. doi: 10.1186/s12862-015-0534-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Watase K., Zoghbi H.Y. Modelling brain diseases in mice: The challenges of design and analysis. Nat. Rev. Genet. 2003;4:296–307. doi: 10.1038/nrg1045. [DOI] [PubMed] [Google Scholar]
  • 12.Nielsen S.M.B., Vinther-Jensen T., Jørgen E., Nielsen J.E., Nørremølle A., Hasholt L., Hjermind L.E., Josefsen K. Liver function in Huntington’s disease assessed by blood biochemical analyses in a clinical setting. J. Neurol. Sci. 2016;362:326–332. doi: 10.1016/j.jns.2016.02.018. [DOI] [PubMed] [Google Scholar]
  • 13.Stüwe S.H., Goetze O., Lukas C., Klotz P., Hoffmann R., Banasch M., Orth M., Schmidt W.E., Gold R., Saft C. Hepatic mitochondrial dysfunction in manifest and premanifest Huntington disease. Neurology. 2013;80:743–746. doi: 10.1212/WNL.0b013e318282514e. [DOI] [PubMed] [Google Scholar]
  • 14.Farshbaf M.J., Ghaedi K. Huntington’s Disease and Mitochondria. Neurotox. Res. 2017;32:518–529. doi: 10.1007/s12640-017-9766-1. [DOI] [PubMed] [Google Scholar]
  • 15.Carvalho C.C.C.R., Caramujo M.J. The Various Roles of Fatty Acids. Molecules. 2018;23:2583. doi: 10.3390/molecules23102583. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Ravaut G., Legiot A., Bergeron K.-F., Mounier C. Monounsaturated Fatty Acids in Obesity-Related Inflammation. Int. J. Mol. Sci. 2021;22:330. doi: 10.3390/ijms22010330. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Summers S.A. Ceramides in insulin resistance and lipotoxicity. Prog. Lipid Res. 2006;45:42–72. doi: 10.1016/j.plipres.2005.11.002. [DOI] [PubMed] [Google Scholar]
  • 18.Herpen N.A., Schrauwen-Hinderling V.B. Lipid accumulation in non-adipose tissue and lipotoxicity. Physiol. Behav. 2008;94:231–241. doi: 10.1016/j.physbeh.2007.11.049. [DOI] [PubMed] [Google Scholar]
  • 19.Saltiel A.R., Olefsky J.M. Inflammatory mechanisms linking obesity and metabolic disease. J. Clin. Investig. 2017;127:1–4. doi: 10.1172/JCI92035. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Nilsen D.W.T., Myhre P.L., Kalstad A., Schmidt E.B., Arnesen H., Seljeflot I. Serum Levels of Dihomo-Gamma (γ)-Linolenic Acid (DGLA) Are Inversely Associated with Linoleic Acid and Total Death in Elderly Patients with a Recent Myocardial Infarction. Nutrients. 2021;13:3475. doi: 10.3390/nu13103475. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Jacqueline K.I., Calder P.C. Omega-6 fatty acids and inflammation. Prostaglandins Leukot. Essent. Fat. Acids. 2018;132:41–48. doi: 10.1016/j.plefa.2018.03.004. [DOI] [PubMed] [Google Scholar]
  • 22.Valadão P.A.C., Santos K.B.S., Ferreira E., Vieira T.H., Macedo E., Cordeiro T., Teixeira A.L., Guatimosim C., de Miranda A.S. Inflammation in Huntington’s disease: A few new twists on an old tale. J. Neuroimmunol. 2020;15:577348–577380. doi: 10.1016/j.jneuroim.2020.577380. [DOI] [PubMed] [Google Scholar]
  • 23.Mooli R.G.R., Ramakrishnan S.K. Liver Steatosis is a Driving Factor of Inflammation. Cell. Mol. Gastroenterol. Hepatol. 2022;13:1267–1270. doi: 10.1016/j.jcmgh.2022.01.007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Mielcarek M., Toczek M., Smeets C.J.L.M., Franklin S.A., Bondulich M.K., Jolinon N., Muller T., Ahmed M., Dick J.R.T., Piotrowska I., et al. HDAC4-myogenin axis as an important marker of HD-related skeletal muscle atrophy. PLoS Genet. 2015;11:e1005021. doi: 10.1371/journal.pgen.1005021. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Toczek M., Zielonka D., Zukowska P., Marcinkowski J.T., Slominska E., Isalan M., Smolenski R.T., Mielcarek M. An impaired metabolism of nucleotides underpins a novel mechanism of cardiac remodeling leading to Huntington’s disease related cardiomyopathy. Biochim. Biophys. Acta. 2016;1862:2147–2157. doi: 10.1016/j.bbadis.2016.08.019. [DOI] [PubMed] [Google Scholar]
  • 26.Tomczyk M., Glaser T., Slominska E.M., Ulrich H., Smolenski R.T. Purine Nucleotides Metabolism and Signaling in Huntington’s Disease: Search for a Target for Novel Therapies. Int. J. Mol. Sci. 2021;22:6545. doi: 10.3390/ijms22126545. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Tomczyk M., Glaser T., Ulrich H., Slominska E.M., Smolenski R.T. Huntingtin protein maintains balanced energetics in mouse cardiomyocytes. Nucleosides Nucleotides Nucleic Acids. 2022;41:231–238. doi: 10.1080/15257770.2020.1815769. [DOI] [PubMed] [Google Scholar]
  • 28.Valadão P.A.C., da Silva Oliveira B., Joviano-Santos J.V., Vieira E.L.M., Rocha N.P., Teixeira A.L., Guatimosim C., de Miranda A.S. Inflammatory changes in peripheral organs in the BACHD murine model of Huntington’s disease. Life Sci. 2019;232:116653. doi: 10.1016/j.lfs.2019.116653. [DOI] [PubMed] [Google Scholar]
  • 29.Hsiao H.Y., Chen Y.C., Chen H.M., Tu P.H., Chern Y. A critical role of astrocyte-mediated nuclear factor-κB-dependent inflammation in Huntington’s disease. Hum. Mol. Genet. 2013;22:1826–1842. doi: 10.1093/hmg/ddt036. [DOI] [PubMed] [Google Scholar]
  • 30.Risé P., Eligini S., Ghezzi S., Colli S., Galli C. Fatty acid composition of plasma, blood cells and whole blood: Relevance for the assessment of the fatty acid status in humans. Prostaglandins Leukot. Essent. Fat. Acids. 2007;76:363–369. doi: 10.1016/j.plefa.2007.05.003. [DOI] [PubMed] [Google Scholar]
  • 31.Block R.C., Dorsey R., Beck C.A., Brenna J.T., Shoulson I. Altered cholesterol and fatty acid metabolism in Huntington disease. J. Clin. Lipidol. 2010;4:17–23. doi: 10.1016/j.jacl.2009.11.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Wei Y., Liu M., Li X., Liu J., Li H. Origin of the Autophagosome Membrane in Mammals Biomed. Res. Int. 2018:1012789. doi: 10.1155/2018/1012789. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Iuliano M., Seeley C., Sapp E., Jones E.L., Martin C., Li X., DiFiglia M., Kegel-Gleason K.B. Disposition of Proteins and Lipids in Synaptic Membrane Compartments Is Altered in Q175/Q7 Huntington’s Disease Mouse Striatum. Front. Synaptic. Neurosci. 2021;13:618391. doi: 10.3389/fnsyn.2021.618391. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Crotti A., Glass C.K. The choreography of neuroinflammation in Huntington’s disease. Trends Immunol. 2015;36:364–373. doi: 10.1016/j.it.2015.04.007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Rocha N.P., Ribeiro F.M., Furr-Stimming E., Teixeira A.L. Neuroimmunology of Huntington’s Disease: Revisiting Evidence from Human Studies. Mediat. Inflamm. 2016:8653132. doi: 10.1155/2016/8653132. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Björkqvist M., Wild E.J., Thiele J., Silvestroni A., Andre R., Lahiri N., Raibon E., Lee R.V., Benn C.L., Soulet D. A novel pathogenic pathway of immune activation detectable before clinical onset in Huntington’s disease. J. Exp. Med. 2008;205:1869–1877. doi: 10.1084/jem.20080178. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Nakajima H., Fujita S., Kakae M., Nagayasu K., Oh-Hora M., Shirakawa H., Kaneko S. Orai2 channel regulates prostaglandin E2 production in TNFα/IL1α-stimulated astrocytes. Glia. 2022;70:1666–1680. doi: 10.1002/glia.24188. [DOI] [PubMed] [Google Scholar]
  • 38.Lin D., Lei L., Liu Y., Zhang Y., Hu B., Bao G., Song Y., Jin Z., Liu C., Mei Y., et al. Membrane IL1α Inhibits the Development of Hepatocellular Carcinoma via Promoting T- and NK-cell Activation. Cancer Res. 2016;76:3179–3188. doi: 10.1158/0008-5472.CAN-15-2658. [DOI] [PubMed] [Google Scholar]
  • 39.Brouwers H., Jónasdóttir H.S., Kuipers M.E., Kwekkeboom J.C., Auger J.L., Gonzalez-Torres M., López-Vicario C., Clària J., Freysdottir J., Hardardottir I. Anti-Inflammatory and Proresolving Effects of the Omega-6 Polyunsaturated Fatty Acid Adrenic Acid. J. Immunol. 2020;205:2840–2849. doi: 10.4049/jimmunol.1801653. [DOI] [PubMed] [Google Scholar]
  • 40.Dyall S.C., Balas L., Bazan N.G., Brenna J.T., Chiang N., da Costa Souza F., Dalli J., Durand T., Galano J.-M., Lein P.J., et al. Polyunsaturated fatty acids and fatty acid-derived lipid mediators: Recent advances in the understanding of their biosynthesis, structures, and functions. Prog. Lipid Res. 2022;86:101165. doi: 10.1016/j.plipres.2022.101165. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.Gozdzik P., Czumaj A., Sledzinski T., Mika A. Branched-chain fatty acids affect the expression of fatty acid synthase and C-reactive protein genes in the hepatocyte cell line. Biosci. Rep. 2023;43:BSR20230114. doi: 10.1042/BSR20230114. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.Chiang M.C., Chern Y., Juo C.G. The dysfunction of hepatic transcriptional factors in mice with Huntington’s Disease. Biochim. Biophys. Acta. 2011;1812:1111–1120. doi: 10.1016/j.bbadis.2011.05.006. [DOI] [PubMed] [Google Scholar]
  • 43.Woodman B., Butler R., Landles C., Lupton M.K., Tse J., Hockly E., Moffitt H., Sathasivam K., Bates G.P. The Hdh Q150/Q150 knock-in mouse model of HD and the R6/a exon 1 model develop comparable and widespread molecular phenotypes. Brain Res. Bull. 2007;72:83–97. doi: 10.1016/j.brainresbull.2006.11.004. [DOI] [PubMed] [Google Scholar]
  • 44.Lin C.H., Tallaksen-Greene S., Chien W.M., Cearley J.A., Jackson W.S., Crouse A.B., Ren S., Li X.-J., Albin R.L., Detloff P.J. Neurological abnormalities in a knock-in mouse model of Huntington’s disease. Hum. Mol. Genet. 2001;10:137–144. doi: 10.1093/hmg/10.2.137. [DOI] [PubMed] [Google Scholar]
  • 45.Folch J., Lees M., Sloane Stanley G.H. A simple method for the isolation and purification of total lipides from animal tissues. J. Biol. Chem. 1957;226:497–509. doi: 10.1016/S0021-9258(18)64849-5. [DOI] [PubMed] [Google Scholar]
  • 46.Martinez-Montoro J.I., Nunez-Sanchez M.A., Martinez-Sanchez M.A., Balaguer-Roman A., Fernandez-Ruiz V.E., Ferrer-Gomez M., Sledzinski T., Frutos M.D., Fernandez-Garcia J.C., Mika A., et al. Hepatic and serum branched-chain fatty acid profile in patients with nonalcoholic fatty liver disease: A case-control study. Obesity. 2023;31:1064–1074. doi: 10.1002/oby.23711. [DOI] [PubMed] [Google Scholar]

Associated Data

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

Supplementary Materials

ijms-26-07304-s001.zip (87.6KB, zip)

Data Availability Statement

The datasets and materials used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

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