Pathophysiological Mechanisms Linking Obstructive Sleep Apnea to Nonalcoholic Fatty Liver Disease

Article information

Sleep Med Res. 2025;16(2):93-102

Publication date (electronic) : 2025 June 26

doi : https://doi.org/10.17241/smr.2025.02859

Eptehal Mohammed Dongol, MD ¹

, Fatma Rabea Ahmed Hamdan, MSc^,²

, Omyma Galal Ahmed, MD, PhD ³

, Rehab Hemdan Abdel-Aziz, MD ²

, Mahitab Younes, MBBCh ⁴

, Rana Toghan Ahmed, MD ²

¹Department of Chest, Qena Faculty of Medicine, South Valley University, Qena, Egypt

²Department of Physiology, Qena Faculty of Medicine, South Valley University, Qena, Egypt

³Department of Physiology, Assiut Faculty of Medicine, Assiut University, Assiut, Egypt

⁴Qena Faculty of Medicine, South Valley University, Qena, Egypt

Corresponding Author Fatma Rabea Ahmed Hamdan, MD Department of Physiology, Qena Faculty of Medicine, South Valley University, 7 Moawea St., Qena 83523, Egypt Tel +201099544675 Fax +20963226432 E-mail F_r_hamdan@yahoo.com

Received 2025 April 17; Revised 2025 May 20; Accepted 2025 May 28.

Abstract

Sleep plays a crucial biological role and is responsible for overall well-being. Poor sleep is associated with several negative health conditions. Sleep fragmentation and chronic intermittent hypoxia in patients with obstructive sleep apnea can lead to several negative health effects, including a collection of metabolic disorders known as “metabolic syndrome,” which includes the development of non-alcoholic fatty liver disease. Decreased O2 at the tissue level leads to the development of adaptive mechanisms, including hypoxia-induced signalling as hypoxia-inducible factors, stress responses as endoplasmic reticulum stress, and autophagy by reactive oxygen species. In addition to this, disrupted gut barrier integrity, increased gut permeability, dyslipidemia, and insulin resistance have a pathologic role in non-alcoholic fatty liver disease development. The prognosis of non-alcoholic fatty liver disease in obstructive sleep apnea is a multifactorial process. Our review will clarify the complex and multifactorial pathophysiological mechanisms that contribute to the development of non-alcoholic fatty liver disease in patients with obstructive sleep apnea, as well as how the condition may progress to non-alcoholic steatohepatitis.

Keywords: Non-alcoholic fatty liver disease; Obstructive sleep apnea; Metabolic syndrome; Hypoxia; Sleep fragmentation

INTRODUCTION

Sleep plays a crucial biological role and is increasingly acknowledged for its impact on overall well-being [1,2]. Poor sleep is associated with several negative health consequences, such as cardiovascular disease, metabolic syndrome (MetS), and higher mortality rates. Additionally, inadequate sleep leads to significant economic costs due to decreased productivity and increased healthcare utilization [3,4].

Obstructive sleep apnea (OSA) is a chronic disorder; its main feature is repeated events of upper airway collapse, interrupting sleep, resulting in airflow obstruction, either partially (hypopnea) or completely (apnea). These episodes frequently trigger sleep disruptions, arousals, and intermittent drops in blood oxygen levels, contributing to fragmented sleep and intermittent hypoxia [5,6].

OSA is linked to several negative health effects, including a collection of metabolic disorders known as MetS. This syndrome includes conditions such as hypertension, impaired glucose metabolism, insulin resistance (IR), atherosclerosis, and dyslipidemia [7].

Epidemiological studies show that OSA prevalence ranges from 9% to 38% in the adult population. Also, its incidence is higher in men than in women. Additionally, about 80%–90% of subjects with OSA remain undiagnosed [8]. The estimates for prevalence vary among different groups, including those who are overweight or obese, individuals from minority racial backgrounds, and older adults [9].

Polysomnography is the definitive test used to assess and diagnose OSA severity, measured by the apnea-hypopnea index (AHI). The AHI is categorized as follows: normal (if AHI <5), mild (if 5≤AHI<15), moderate (if 15≤AHI<30), and severe (if AHI ≥30) [10].

The connection between sleep disorders and MetS is bidirectional. For instance, in OSA patients, there is an increased risk of developing diabetes mellitus (DM), which is a component of MetS, independent of body fat. Additionally, research has demonstrated that both the frequency and severity of sleep apnea are elevated in individuals with DM type II. This suggests a widespread occurrence of OSA among the general public and its possible association with new-onset diabetes [11,12].

Additionally, sleep fragmentation (SF) and chronic intermittent hypoxia (CIH) in patients with OSA can lead to non-alcoholic fatty liver disease (NAFLD) development [13,14]. NAFLD is a complex metabolic condition and is the most common chronic liver disease affecting both adults and children. It has a prevalence rate of approximately 30%–50% in the general population, but this rate rises to around 80% among individuals with diabetes or obesity [15].

The accumulation of fat within hepatocytes causes liver tissue damage that is unrelated to alcohol consumption or other specific liver injury factors. This damage progresses in stages: stage 1 is simple hepatic steatosis, followed by stage 2, which is nonalcoholic steatohepatitis (NASH), potentially advancing to stage 3, fibrosis. Ongoing inflammation can lead to scarring in the liver, culminating in stage 4, cirrhosis, which is considered the most severe form of the disease [16].

Our review will clarify the complex and multifactorial pathophysiological mechanisms that contribute to NAFLD development in OSA patients and how the condition may progress to NASH.

POSSIBLE PATHOPHYSIOLOGICAL MECHANISMS

The following sections explore the possible pathophysiological mechanisms that mediate the association between OSA and NAFLD. These interrelated pathways are summarized schematically in Fig. 1.

Fig. 1.

Schematic representation of the potential mechanisms linking obstructive sleep apnea (OSA) to non-alcoholic fatty liver disease (NAFLD). Chronic intermittent hypoxia (CIH) and sleep fragmentation (SF), as hallmarks of OSA, trigger oxidative stress and inflammation via pathways including endoplasmic reticulum stress (ERS) and hypoxia-inducible factor 1-alpha (HIF-1α) activation. These processes contribute to insulin resistance (IR), dyslipidemia, and gut barrier dysfunction. SF also increases sympathetic activity, hypothalamic-pituitary-adrenal (HPA) axis activation, and circulating cortisol and adrenaline levels. The cumulative effect of these changes promotes toxic lipid accumulation in the liver, ultimately leading to the development of NAFLD. Different arrow styles were used solely to visually differentiate overlapping pathways and improve clarity, especially given the complex interactions illustrated. They do not reflect differences in the strength or nature of the relationships.

Hypoxia-Inducible Factor 1-α

Oxygen is essential for living cells to provide the needed adenosine 5’-triphosphate necessary for many actions in the cell and is involved in various metabolic processes and cellular protein functions. The development of CIH due to OSA decreased O2 at the tissue leading to the stimulation of adaptive mechanisms including hypoxia-induced signalling (as hypoxia-inducible factors [HIFs]), stress responses, endoplasmic reticulum (ER), autophagy by reactive oxygen species (ROS), and others. These adaptive mechanisms promote modifications in metabolism to match the oxygen availability [17,18].

During normoxia, hypoxia-inducible factor 1-alpha (HIF-1α) proteins undergo hydroxylation and subsequent degeneration. After hydroxylation, HIF-1α interacts with pVHL and then promotes ubiquitin-proteasome degradation of HIF-1α. When hypoxia occurs, the enzymatic activity of PHD is inhibited, which stops the process of HIF-1α hydroxylation in addition to ubiquitin-mediated proteasome degradation. Afterwards, the HIF-1α subunit interacts with HIF-1β to form a transcriptional complex dimerization which enters the nucleus and binds with HERs. This combination promotes several downstream gene expressions to maintain oxygen homeostasis at the cell [19,20].

OSA leads to a state of generalized CIH. Some studies have recorded an elevation in HIF-1α levels in OSA patients, and this elevation is related to OSA severity as evaluated by the AHI [21,22].

Recent studies suggest that HIF-1α plays a significant role in the onset and prognosis of various liver diseases, including NAFLD. HIF-1α may participate in complex signalling pathways that regulate its expression across different liver disease processes [23,24]. One metabolic change associated with HIF-1α overexpression is the activation of genes that favour glucose uptake and glycolysis, such as the GLUT1 and GLUT3 glucose transporters. These enhance glucose uptake by hepatocytes, and glycolysis produces more substrates (e.g., pyruvate) for lipogenesis, resulting in triglyceride accumulation. Additionally, HIFs not only trigger de novo lipogenesis (DNL) but also suppress fatty acid β-oxidation as well as stimulate the uptake of free fatty acids (FFAs), promoting toxic lipid accumulation at liver cells and inducing hepatic steatosis [23,25,26]. Additionally, the hypertrophy of adipose tissue produces local tissue hypoxia, which increases the HIF-1α serum level [27].

Elevated levels of HIF-1α can lead to inflammatory responses and an increased production of ROS, both of which contribute to IR development [28]. Increased expression of HIF-1α is not only a stimulator of the establishment of NAFLD but is also implicated in the prognosis of NASH through inflammation [29]. HIF-1α can regulate the secretion of LOX, an enzyme that mediates the cross-linking of extracellular matrix proteins and is involved in NASH-related fibrosis [30].

In addition to HIF-1α, the activation of HIF-2α contributes to hepatic steatosis, inflammation, and fibrosis [31]. It was suggested that CIH decreases HIF-2α level, but recent studies proved that hypoxia can mediate HIF-2α upregulation [32,33]. Chronic activation of HIF-2α in adults is associated with severe hepatic steatosis. This condition is characterized by decreased expression of lipogenic genes, impaired fatty acid β-oxidation, and an increased ability to store lipids, potentially through the regulation of CD36 expression and activity. HIF-2α activation in the liver is essential for maintaining liver homeostasis and further contributes to disease progression [34]. Furthermore, HIF-2α-deficient mice show reduced CD36 expression and exhibit more characteristics of NASH [35].

Briefly, CIH, a characteristic of OSA, elevates the level of HIF-1α, and this increase is associated with the severity of OSA. HIF-1α induces hepatic steatosis, stimulating DNL, FFA uptake, IR, and oxidative stress as illustrated in Fig. 2. Both HIF-1α and HIF-2α are involved in the prognosis of NAFLD to NASH.

Fig. 2.

Schematic representation of the molecular mechanisms linking obstructive sleep apnea (OSA) and the progression of non-alcoholic fatty liver disease (NAFLD) to nonalcoholic steatohepatitis (NASH) via hypoxia-inducible factor 1-alpha (HIF-1α). Chronic intermittent hypoxia (CIH), a hallmark of OSA, leads to increased expression of HIF-1α, which orchestrates several metabolic and inflammatory pathways contributing to hepatic lipid accumulation and disease progression. HIF-1α enhances glucose uptake by upregulating GLUT1 and GLUT3, promoting lipogenesis and triglyceride accumulation. It also increases free fatty acid (FFA) uptake, suppresses fatty acid β-oxidation, and induces reactive oxygen species (ROS) and inflammatory responses, all leading to toxic lipid accumulation and insulin resistance (IR). These changes facilitate the development of NAFLD. Moreover, local tissue hypoxia due to hepatic steatosis further upregulates HIF-1α, creating a vicious cycle that promotes progression to NASH, aided by LOX activation and fibrosis.

IR

Multiple metabolic changes are responsible for the development of IR, including hyperinsulinemia, hyperglycemia, elevated FFAs levels, and also proinflammatory cytokines levels, that may compromise insulin signalling in many tissues [36]. IR is prevalent in NAFLD patients and has been thought to be an important contributing factor in the progression from a simple form of steatosis to NASH, together with lifestyle, gut microbiota changes, and genetic susceptibility [37]. The etiopathogenesis of IR in NAFLD patients involves elevated levels of FFAs resulting from impaired lipolysis in adipose tissue. and a diet rich in high-saturated FFAs deranges insulin signalling and results in IR [38,39]. Additionally, CIH in OSA results in dysfunction of gut microbiota and increased intestinal permeability, producing changes in circulating exosome composition, all contributing to adipocyte dysfunction and subsequently enhancing IR [40]. CIH also results in HIF-1α upregulation in various organs, including pancreatic beta cells. Higher levels of HIF-1α may cause inflammatory responses and enhance ROS production, which contributes to IR [28]. Moreover, sleep disturbance associated with OSA causes marked activity of the sympathetic nervous system, stimulation of the hypothalamic-pituitary-adrenal (HPA) axis, and oxidative stress, each of which reduces insulin-stimulated glucose uptake and secretion. This results in increased ROS levels, inflammation, and apoptosis of pancreatic beta cells, ultimately leading to decreased glucose tolerance and IR [41].

In IR, liver fat deposition occurs as a result of defective FFA uptake, synthesis, exportation, and oxidation. In the case of NAFLD patients, the hepatic steatosis severity correlates with elevated FFA levels in the plasma due to the inability to inhibit lipolysis in adipose tissue, as subcutaneous adipose tissue is a significant source of intrahepatic fat, and it accounts for approximately 62%–82% of triglycerides inside liver cells. This process is not found in non-obese, non-diabetic NAFLD patients, so it is considered diabetes and obesity independent, as IR influences hepatic glucose output, glucose uptake (e.g., glucose oxidation and glycogen synthesis), lipolysis, and lipid oxidation. Visceral fat, although not the dominant origin of plasma FFAs, is a prominent source of inflammatory cytokines that are transported to the liver; this is evidenced by the correlation between both IL-6 and C-reactive protein levels in the portal vein. Under the state of IR, the liver is unable to retain its capacity to suppress these processes [42]. Moreover, insulin receptor substrate (IRS) proteins are significant in the pathogenesis of NAFLD. Among the four types of IRS proteins that exist in mammals, both IRS1 and IRS2 play particularly crucial roles in metabolic function regulation [43]. OSA severity is now correlated with insulin sensitivity of adipose tissue and its capacity to induce or amplify IR by way of FFA-induced alteration of turn IR in postulation as the initial pathologic event toward NAFLD initiation and development of NASH [37,44]. Fig. 3 summarizes the possible pathways linking OSA to IR and NAFLD.

Fig. 3.

Pathways linking obstructive sleep apnea (OSA) to insulin resistance (IR) and non-alcoholic fatty liver disease (NAFLD). OSA, through chronic intermittent hypoxia (CIH) and sleep fragmentation (SF), contributes to IR by increasing oxidative stress, inflammation, and sympathetic activity. CIH causes gut dysbiosis leading to adipose tissue dysfunction, enhanced lipolysis, and elevated free fatty acids (FFAs). Also, CIH increases hypoxia-inducible factor 1-alpha (HIF-1α) level, promoting ROS and β-cell dysfunction. SF raises sympathetic tone and further oxidative stress, impairing insulin action. Visceral fat also releases inflammatory cytokines (e.g., IL-6, CRP), exacerbating liver IR and fat accumulation, progressing from simple steatosis to NAFLD.

Gut Barrier Dysfunction

The mucosal surface of the gastrointestinal tract acts as an immune barrier, with intercellular tight junctions that prevent bacterial translocation and the leakage of toxic metabolites into the bloodstream under normal conditions. Thus, the gut is essential for nutrient absorption and protects against numerous pathogens. The intestinal barrier is a component of the gut-liver axis, which involves a bidirectional connection among the microbiome, gut, portal vein, liver, biliary tree, systemic circulation, and various systemic mediators [45].

CIH, accompanied by reoxygenation, has the potential to disrupt the gut barrier in individuals with OSA, independent of metabolic dysregulation. This injury to the gut wall allows microbes and macromolecules to penetrate the bloodstream, triggering both hepatic and systemic inflammation [46,47]. Recently, some evidence indicates that gut dysbiosis contributes to the translocation of bacterial components, which can cause liver injury in the pathogenesis of NAFLD [48].

Notably, the gut microbiota changes significantly in mice exposed to CIH, accompanied by systemic inflammation [49]. Metabolic pathway analyses show that CIH primarily affects the microbiota involved in bile acid and fatty acid metabolism. Additionally, a recent study records a variation in the structure and composition of intestinal microbiota among patients depending on OSA severity. Consequently, dysbiosis of the gut microbiome is involved in systemic inflammation and metabolic disease and is a mediator for CIH [50,51]. This condition leads to disrupted gut barrier integrity and increased gut permeability, which induces injury to the liver during NAFLD development [49].

Furthermore, SF associated with OSA can produce changes in the intestinal lumen, resulting in increased microbial diversity, elevated inflammatory mediators, in addition to greater bacterial translocation [52]. Therefore, sleep disruption can modify the gut microbiota, promoting hepatic and systemic inflammation as well as changes in metabolic processes [53]. There is accumulating evidence of elevated levels of biomarkers indicating gut barrier disruption (e.g., I-FABP, LPS, D-LA, and LBP) in patients with OSA [54]. Fig. 4 illustrates the mechanistic pathway linking OSA to the development of NAFLD via gut dysbiosis and intestinal barrier dysfunction.

Fig. 4.

Mechanistic pathway linking obstructive sleep apnea (OSA) to the development of non-alcoholic fatty liver disease (NAFLD) via gut dysbiosis and intestinal barrier dysfunction. OSA, through chronic intermittent hypoxia (CIH) and sleep fragmentation (SF), induces gut dysbiosis and disrupts the gut barrier. Dysbiosis alters microbial populations involved in bile acid and fatty acid metabolism and promotes the translocation of bacterial components, contributing to hepatic and systemic inflammation. Simultaneously, gut barrier disruption increases levels of I-FABP, LPS, D-LA, and LBP, leading to enhanced gut permeability and allowing microbes and macromolecules to enter the bloodstream. These changes collectively drive hepatic and systemic inflammation, which ultimately contributes to the progression of NAFLD.

Dysfunction of gut microbiota and systemic inflammation induce the prognosis of NAFLD and also irritable bowel syndrome (IBS), as recent studies suggest that there is an association between both NAFLD and IBS [55-57]. Also, there is a high prevalence rate of OSA among IBS patients [56,58].

Endoplasmic Reticulum Stress

Endoplasmic reticulum stress (ERS) is a potential pathway by which CIH induces oxidative stress in the case of NAFLD. CIH triggers the ERS pathway, resulting in the derangement of lipid homeostasis in hepatocytes and toxic lipids generation [59]. This results in ERS and activation of the unfolded protein response (UPR) [31]. Normally, transmembrane proteins are synthesized within the ER and remain there until properly folded and can be secreted. However, the presence of either misfolded or unfolded proteins induces ERS, which consequently leads to the activation of UPR as a final resort for terminating this stress and restoring the balance [60]. Excessive activation of the UPR can lead to pathological states like hepatocellular injury and apoptosis. The UPR is mediated by three types of transducer proteins, which are ER integral membrane proteins: ATF6, IRE1, and PERK [61]. The proteins are typically kept in a repressed condition by intraluminal chaperones of the ER, such as BiP or GRP78. Throughout UPR, BiP associates with the misfolded proteins, resulting in the dissociation of these three ER transmembrane transducers and stimulation their activation [62,63]. When adaptive responses are saturated, the ER folding capacity cannot be recovered, and this results in over-activation of the UPR, yielding disease conditions such as apoptosis through CHOP transcription factor activation, JNK, and caspases [64,65]. ERS, and its three divisions, are highly involved in the NAFLD prognosis. Each branch has a unique interaction with mechanisms like lipotoxicity, pyroptosis, autophagy, and apoptosis, which helps in the development of NAFLD to NASH and eventually hepatocellular carcinoma [66]. This consequence is summarized in Fig. 5.

Fig. 5.

Mechanistic pathway linking obstructive sleep apnea (OSA)-induced chronic intermittent hypoxia (CIH) to endoplasmic reticulum (ER) stress and its role in non-alcoholic fatty liver disease (NAFLD) progression. CIH, a hallmark of OSA, promotes the generation of toxic lipids and the accumulation of unfolded proteins in the endoplasmic reticulum (ER), triggering endoplasmic reticulum stress (ERS). This activates the unfolded protein response (UPR) via three key signaling branches: PERK, ATF6, and IRE1. When ER folding capacity is restored, UPR functions adaptively to alleviate stress and restore cellular homeostasis. However, persistent or excessive ER stress leads to prolonged UPR activation, causing lipotoxicity, pyroptosis, autophagy, and apoptosis through downstream mediators such as CHOP, JNK, and caspases. These maladaptive responses contribute to hepatocellular injury and the progression from NAFLD to nonalcoholic steatohepatitis (NASH).

Recent studies have also indicated that the UPR is one of the cellular response mechanisms to hypoxia and that PERK is the hypoxia-related kinase responsible for eIF2α phosphorylation [67]. In addition, numerous studies found a link between the UPR with lipogenesis regulation and hepatic steatosis [68,69]. To what extent the UPR causes hepatic steatosis would rely on the relative response and activation of the three transducer proteins: ATF6, IRE1α, and PERK. Activation of JNK by IRE1α can lead to injury of the liver and stimulation of apoptosis of hepatocytes, which are the characteristic features of NAFLD [66].

Oxidative Stress

The experimental findings revealed that CIH is linked with the injury of the liver via increased levels of oxidative stress and lipid peroxidation. Current evidence indicates CIH is the main cause of oxidative stress in the liver and a critical factor in NAFLD pathogenesis among patients with OSA [70]. CIH changes the function and organization of hepatic mitochondria by enhancing DNA damage in addition to the production of ROS, producing an imbalance between antioxidant defences and oxidative stress [71]. Oxidative stress has been unequivocally implicated in either pediatric or adult NAFLD, also evidenced in experimental rodent models, proposing that it enhances disease progression [72,73]. In experimental research of NAFLD, oxidative stress is suggested to be caused by enhancing ROS generation by several critical factors including mitochondrial dysfunction due to toxic accumulation of FFA, enhanced FFA metabolism in the ER by cytochrome P450 isoforms 2E1 and 4A, ERS, lipotoxicity, hypoxia, and ROS production by NADPH oxidase isoforms which is involved in ligand-receptor interactions (e.g., growth factors, cytokines, adipokines, and chemokines) or inflammatory cells activation [72,73]. This oxidative injury causes direct injury to DNA, lipids, and proteins that subsequently initiate cell death signalling cascades and impairment of hepatocyte function and viability. Also, ROS can increase redox-sensitive transcription factor activation like NF-κB in addition to HIF-1α, which augments the expression of both inflammatory and fibrogenic mediators by hepatic stellate cells and Kupffer cells, leading to aggravating the progression of NAFLD. Regardless of the cause, ROS and oxidative stress are internationally recognized to be pathogenetically involved in NAFLD development [70]. Additionally, the NF-κB signalling pathway induces the transcription of cytokine genes and increases inflammatory factor expression, such as IL-6 and TNF-α, which play a vital role in hepatic steatosis and are primarily responsible for neutrophil sequestration in the liver, directly mediating tissue damage. CIH thus promotes NAFLD development and progression by inducing the oxidative stress response in addition to activating a cascade of reactions involving NF-κB pathways [74]. Also, high levels of HIF-1α have been known to induce inflammation and increase ROS production, which are contributors to the development of IR, creating a vicious cycle [28].

Dyslipidemia

OSA and dyslipidemia have a strong bidirectional relationship, and recent research shows a positive association between OSA severity and the occurrence of dyslipidemia in affected individuals [75]. CIH, SF, and increased sympathetic activity may lead to lipid dysregulation.

CIH contributes to augmenting lipolysis in fat tissue, raising the plasma concentration of FFAs, activating lipogenesis in the liver, delaying the clearance of postprandial lipids, and suppressing the lipids’ mitochondrial oxidation. CIH enhances lipid transport from the adipose tissue to the liver via upregulating various proteins, including SREBP-1c, stearoyl-CoA desaturase-1, ACC, and FAS [76].

Also, CIH initiates and exacerbates NAFLD by producing an imbalance state between lipid breakdown and synthesis, thus ending up with the hepatic storage of fat [77]. In addition to DNL and FFA oxidation, CIH also affects the uptake of fatty acids [78]. The liver in NAFLD patients demonstrates increased plasma lipid uptake, primarily FFAs and lipoproteins. This action is suggested to stimulate the biosynthesis of hepatic lipid by stimulating lipid synthesis genes, such as fatty acid translocase CD36 and stearoyl-CoA desaturase-1, thereby stimulating FFA uptake in the liver [79]. Intracellular lipid accumulation due to hypoxia may be linked to β-oxidation suppression and increased FFA uptake more than DNL [80].

Also, increased sympathetic tone resulting from CIH and SF plays an important role in lipid metabolic disturbances, as noradrenaline and cortisol can influence levels of hormone-sensitive lipoprotein and alter HDL synthesis [80]. Fig. 6 illustrates the pathophysiological link between OSA and dyslipidemia contributing to NAFLD.

Fig. 6.

Pathophysiological link between obstructive sleep apnea (OSA)-related chronic intermittent hypoxia (CIH)/sleep fragmentation (SF) and dyslipidemia contributing to non-alcoholic fatty liver disease (NAFLD). CIH and SF, characteristic features of OSA, increase sympathetic tone and elevate levels of stress hormones like adrenaline and cortisol. Also, CIH and SF promote enhanced lipolysis in adipose tissue and delay postprandial lipid clearance, leading to elevated free fatty acids (FFAs) in the circulation. In the liver, increased FFAs uptake and lipoprotein, stimulated de novo lipogenesis (DNL) and suppressed β-oxidation, all these effects collectively result in toxic lipid accumulation, initiating and aggravating NAFLD.

SF

The OSA pathophysiology is characterized by the recurrent collapse of the upper airway during sleep, causing intermittent stoppage of breathing and severe disruption of sleep, affecting the sleep quality and impacting several physiological systems, most notably metabolism [81].

SF can cause circadian rhythm disturbance, which is important to maintain metabolic homeostasis, particularly in the liver. Numerous studies have demonstrated that reduced sleep duration is associated with an increased risk of NAFLD development [82,83].

CIH, a defining characteristic of OSA, has a well-established connection to metabolic abnormalities such as IR, which plays an important role in NAFLD progression. Additionally, interrupted sleep patterns and sleep loss, prevalent in OSA, can exacerbate hepatic inflammation, thereby facilitating NAFLD progression [84].

The pathophysiologic effects of OSA are associated with rhythmic disturbances in sleep cycles. The lipogenesis in the liver and circadian rhythm of insulin release is suggested to be under the control of a transcriptional and translational negative feedback loop mediated by clock genes [85]. Circadian clock dysregulation can increase sympathetic nervous activity, which may reduce insulin sensitivity, resulting in IR, which in turn leads to abnormalities in glucose and lipid metabolism that enhance NAFLD [86]. There is evidence proving that sleep disturbances affect hormone secretion, for example, the prolonged nocturnal release of growth hormone and elevated levels of both adrenaline and noradrenaline in the morning that may induce IR [87]. In addition, sleep deprivation has been shown to elevate cortisol levels and amplify the cortisol awakening response and the HPA axis, which may potentially exacerbate NAFLD [88]. Furthermore, SF appears to amplify NAFLD through gut barrier dysfunction by inhibiting melatonin production, causing oxidative stress as well as inflammatory responses in the gut. Thus, sleep deprivation is involved in NAFLD pathogenesis through many mechanisms, such as disturbances in lipid and glucose metabolism, in addition to stress and proinflammatory responses [89].

In conclusion, a state of dyslipidemia, which is induced by CIH, SF, IR, elevated HIFs, gut barrier dysfunction, and sympathetic stimulation, stimulates DNL and the uptake of FFAs. This leads to toxic lipid accumulation in hepatic cells, “NAFLD.” Accumulated fat induces elevated HIFs, ER stress, inflammation, and oxidative stress, which in turn help in the prognosis of NAFLD and induce NASH. So, it is obvious that the prognosis of NAFLD in OSA is a multifactorial process; many factors contribute to this prognosis and lead to each other, creating a vicious cycle in some cases. Much research is still needed to clarify the integration of these pathophysiological mechanisms.

Notes

Availability of Data and Material

Data sharing not applicable to this article as no datasets were generated or analyzed during the study.

Author Contributions

Conceptualization: Eptehal Mohammed Dongol, Fatma Rabea Ahmed Hamdan. Supervision: Omyma Galal Ahmed. Visualization: Mahitab Younes, Fatma Rabea Ahmed Hamdan. Writing—original draft: Fatma Rabea Ahmed Hamdan, Eptehal Mohammed Dongol. Writing—review & editing: Omyma Galal Ahmed, Rana Tohgan Ahmed, Rehab Hemdan Abdel-Aziz.

Conflicts of Interest

The authors have no potential conflicts of interest to disclose.

Funding Statement

None

Acknowledgements

None

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