NAFLD and Reduced Bone Mineral Density: Comparison
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Please note this is a comparison between Version 2 by Catherine Yang and Version 1 by Anton R Kiselev.

Non-alcoholic fatty liver disease (NAFLD) is reaching epidemic proportions worldwide. Moreover, the prevalence of this liver disease is expected to increase rapidly in the near future, aligning with the rise in obesity and the aging of the population. The pathogenesis of NAFLD is considered to be complex and to include the interaction between genetic, metabolic, inflammatory, and environmental factors. It is well documented that NAFLD is linked to the other conditions common to insulin resistance, such as abnormal lipid levels, metabolic syndrome, and type 2 diabetes mellitus. Additionally, it is considered that the insulin resistance may be one of the main mechanisms determining the disturbances in both bone tissue metabolism and skeletal muscles quality and functions in patients with NAFLD. 

  • non-alcoholic fatty liver disease
  • bone tissue metabolism
  • osteoporosis

1. Vitamin D

The pathogenesis of the mutual influence of hepatic steatosis and bone tissue remodeling processes is a subject for discussion in many recent papers. Most authors believe that the pathogenesis of decreased BMD in NAFLD is multifactorial and, according to the available literature data, is associated with vitamin D deficiency, decreased physical activity, and the release of pro-inflammatory cytokines from the liver that affect bone [3][1].
The role of vitamin D deficiency in bone homeostasis is well known. It was confirmed that patients with NAFLD have lower serum levels of vitamin D, compared with otherwise healthy persons [19][2]. Vitamin D is known to exhibit antifibrotic activity in the liver via inhibiting the proliferation of hepatic stellate cells and the expression of profibrotic mediators, such as platelet growth factor and transforming growth factor beta (TGF-β). Similarly, vitamin D suppresses the expression of collagen, α-smooth muscle actin, and tissue inhibitors of metalloproteinase-1 (TIMP-1). Furthermore, vitamin D exhibits systemic and tissue-specific anti-inflammatory properties by reducing oxidative stress.
An animal study confirmed the antifibrotic effect of 1,25(OH)2D3 (the active form of vitamin D) on the development of NAFLD by inhibiting hepatic stellate cells, thereby suppressing the expression of TGF-β and platelet-derived growth factor [20][3]. An important role of vitamin D deficiency in the development of NAFLD was also shown in a study on diet-induced mice model of NAFLD. It was established that a high-fat diet in combination with vitamin D deficiency was crucial for the development of steatosis, the pathogenetic mechanisms of which in this case included systemic inflammation, changes in the gut microbiota composition, and the development of insulin resistance [21][4]. Additionally, vitamin D supplementation was shown to reduce the progression of NAFLD via reducing inflammation and hepatocyte apoptosis [22][5]. These data may be explained by the ability of an active form of vitamin D to attenuate oxidative stress, and to upregulate the expression of genes encoding antioxidant enzymes [23][6]. Moreover, it was shown that vitamin D supplementation led to a significant increase in B-cell lymphoma 2 (BCL2) gene expression, whereas the expression of all pro-apoptotic genes and TNF-α was decreased [24][7].
Increasing evidence suggests that the beneficial effect of vitamin D in NAFLD at least in part may be attributed to its impact on gut microbiota composition. Thus, in their recent study R. Thomas et al. (2020) demonstrated that the serum levels of 1,25-dihydroxyvitamin D (active form of vitamin D) were correlated with the α-diversity of gut microbiota and butyrate-producing bacteria [25][8]. Additionally, in a high-fat diet-induced rat model of NAFLD X-L, Zhang et al. (2023) showed that intraperitoneal injection of vitamin D promoted a decrease in hepatic lipid accumulation, along with improvement in serum transaminase activity and blood glucose profile [26][9]. Authors attributed this effect to the modulation of gut microbiota leading to the enhancement of tyrosine, tryptophan, and sphingolipid metabolism, as well as arginine biosynthesis.
Taking into account the specific role of vitamin D in systemic inflammation, a large number of clinical studies have focused on examining the dynamics of the liver histological picture in NAFLD following the intake of biological supplements containing the active form of vitamin D. Though recently published meta-analyses did not confirm the presence of any relationship between the intake of vitamin D and the severity of NAFLD [27[10][11],28], authors note that their data should be interpreted with caution, taking into account the low numbers of observed subjects and the lack of confounder adjustments in the included studies. They also indicate the need for further research in order to clarify this issue. Nevertheless, available evidence suggests the beneficial effects of long-term treatment with low-dose vitamin D in young patients with NAFLD without severe liver fibrosis and comorbidities [29,30,31,32,33][12][13][14][15][16].

2. Chronic Inflammation

Chronic inflammation, as one of the factors in NAFLD pathogenesis, seems to be involved in BMD reduction. Lipid overload associated with lipotoxicity triggers an inflammatory cascade mediated by hepatic stellate and dendritic cells, which produce a variety of proinflammatory, procoagulant, and profibrogenic molecules. The so-called sterile inflammation, associated with local damage, leads to liver fibrosis and inflammatory osteoporosis [34][17]. It is known that in patients with NAFLD, the blood concentration of TNF-α is increased; and inhibition of TNF-α, caused by the introduction of pentoxifylline, reduces inflammation of hepatocytes and normalizes liver function [35][18]. Tumor necrosis factor alpha also affects bone metabolism by inhibiting osteoblastogenesis and inducing osteoclasteogenesis, which causes bone loss. In addition, the presence of chronic inflammation is associated with an increase in the level of adipokines (leptin) and prooxidants (oxidized low-density lipoproteins and uric acid), as well as with a decrease in the level of anti-inflammatory cytokines (IL-10) and antioxidants (paraoxonase 1) [36][19]. A group of researchers led by B.L. Ilesanmi-Oyelere (2019) established higher levels of cytokines (interferon alpha-2, interferon gamma, IL-12p70, IL-33) and chemokines (monocyte chemotactic factor-1) in postmenopausal women with osteoporosis [37,38][20][21].
The chronic inflammatory process also contributes to the increased formation of reactive oxygen species. Excessive oxidative stress leads to stimulation of osteoclast differentiation, osteoblast and osteocyte apoptosis, and simultaneous suppression of osteoclast apoptosis and osteoblast differentiation, thereby affecting bone homeostasis [39,40][22][23]. These data may imply that it is chronic inflammation that links NAFLD and osteoporosis, albeit further studies are required to elucidate this relationship [35][18].

3. Gut Microbiota

Data accumulated over the past years suggest that there may be an inextricable relationship between bone homeostasis and gut microbiota. This issue has been investigated in a variety of pathological conditions, including but not limited to obesity [41][24], which is known to be strongly associated with NAFLD. It is believed that gut microbiota may impact on the bone tissue metabolism through the following mechanisms: regulation of nutrient absorption, intestinal permeability, and immune response, as well as synthesis of several metabolites (i.e., short-chain fatty acids [SCFAs]), hormones, or neurotransmitters (i.e., 5-hydroxytryptamine) [42][25]. 
Lipopolysaccharides (LPS), the cell wall component of Gram-negative bacteria, are known to be involved in the activation of the host innate immune response and were shown to play an important role in NAFLD development and progression. The latter may be due to the ability of LPS to drive and maintain systemic low-grade inflammation, also known to be involved in the disturbance of bone tissue metabolism. Lipopolysaccharides can stimulate the secretion of different pro-inflammatory cytokines, in particular IL-1β and TNF-α, thus inducing the expression of the receptor activator of nuclear factor kappa B ligand (RANKL). This results in the activation of bone resorption and inhibition of bone formation [43][26].
Currently, it is suggested that bile acids can be considered as important signal molecules participating in the pathogenesis of NAFLD. Gut microbiota are involved in bile acids metabolism as they promote the formation of secondary bile acids in the intestine. Moreover, through farnesoid X receptor (FXR) and G protein-coupled bile acid receptor 5 (TGR5) signaling, gut microbiota are capable of changing the amounts and type of secondary bile acids, thus influencing their metabolic effects [44][27]. In turn, secondary bile acids, being potent TGR-5 agonists through the stimulation of TGR5, can increase the production of glucagon-like peptide-1 (GLP-1), which can promote the secretion of calcitonin, thus inhibiting bone resorption. Additionally, this hormone can stimulate the proliferation of osteoblasts and inhibit osteoclasts [45][28].
Accumulated data concerning the role of SCFAs in the pathogenesis of NAFLD appear to be controversial. Some studies suggest the beneficial effect of butyrate in the attenuation of NASH due to the modulation of gut microbiota, intestinal barrier function, and the upregulation of the GLP-1 receptor expression, whereas the others indicate that acetate and propionate may promote the progression of NAFLD through the maintenance of low-degree inflammation [46][29]. The production of SCFAs may also be a mechanism by which gut microbiota may influence bone homeostasis. This effect is explained by the ability of SCFAs to increase synthesis and secretion of IGF-1, as well as by the anti-inflammatory action of these molecules through the effect on Tregs development and differentiation [44][27].

4. Diet and Physical Activity

Nowadays, lifestyle modification strategies, including the optimization of nutrition and increase in physical activity, remain the basis of NAFLD treatment. It is well-documented that 5–10% weight loss from the baseline value is associated with the resolution of liver steatosis, inflammation, and fibrosis. Moreover, physical activity itself, irrespective of nutrition modification, may have a beneficial impact on liver disease [47][30]. This may be explained by the hypothesis that skeletal muscle quantity and quality are of great importance for the pathogenesis of NAFLD, a possibility which is receiving more and more attention from the scientific community [48][31]. At the same time, taking into account that bone and muscle tissues are inextricably related to each other both anatomically and functionally, one can conclude that muscle health may also be of great importance for bone homeostasis.
A high-fat diet (HFD) is known to be implicated in NAFLD development and progression. At the same time, data presented in the literature indicate that HFD may have a negative impact on bone density, and this may be due to several mechanisms, including gut microbiota dysbiosis, immune disorders, as well as excess accumulation of adipose tissue [49][32]. It is established that increased dietary fat intake results in the accumulation of adipose tissue in the bone marrow [50][33] and promotes the differentiation of multipotent stem cells (MSCs) into adipocytes rather than osteoblasts, disturbing the bone formation [51][34]. Additionally, obesity is accompanied by a decrease in serum adiponectin concentration, a biologically active substance known to be involved in bone homeostasis.
A high-fat diet may have a negative impact on skeletal muscle quality and function, leading to disturbed energy homeostasis and physical performance. Thus, HC Spooner et al. (2021) demonstrated that HFD was associated with increased extramyocellular fat accumulation accompanied by a decrease in intramyocellular lipid content. These changes resulted in the reduced ability of muscles to utilize fatty acids and provided further deterioration of energy homeostasis induced by HFD [52][35]. It is worth noting that this effect was not accompanied by any changes in body composition.
As to the influence of physical activity on bone mineral density and bone tissue metabolites, similarly to NAFLD, physical exercises may have a beneficial impact on the above-mentioned issues. One recently published systematic review indicated that physical activity appeared to be important for the prevention of osteoporosis in people aged ≥65 years. The greatest effect was demonstrated for the training programs that included multiple exercises and resistance exercises and for high-dose training programs [53][36]. The other systematic review demonstrated that physical activity was able to increase bone formation and decrease bone resorption biomarkers in subjects with osteoporosis [54][37]. However, both reviews indicated the need for further research in this area.

5. Biologically Active Substances

The list of main bone tissue metabolites and their functions, including their role in bone turnover, is presented in Table 1. Table 2 summarizes the data on the association of bone tissue metabolites with the development of liver fibrosis and metabolic disturbances.
Table 1.
Main bone tissue metabolites and their functions.
Biologically Active Substance Encoding Gene Tissue Distribution/Main Sources Functions Role in Bone Tissue Metabolism References
55
]
[
56]
Table 2.
Association of bone tissue metabolites with the development of liver fibrosis and metabolic disturbances.
Biologically Active Substance Possible Role in Liver Diseases Association with Metabolic Syndrome References
Osteopontin (OPN) Secreted phosphoprotein 1 (SPP1) Bone cells (preosteoblasts, osteoclasts/osteoblasts, osteocytes), hepatocytes, epithelial cells, endothelial cells, fibroblasts, renal tubular cells, smooth muscle cells, immune cells (T cells, macrophages, and natural killer cells), malignantly transformed epithelial cell lines
Osteopontin (OPN) Participation in liver fibrosis development and progression via activation of stellate cells Elevated serum level of OPN is associated with metabolic syndrome and its different components (systolic and diastolic blood pressure, fasting blood glucose, serum concentrations of total cholesterol, low density lipoprotein cholesterol [LDL-c], triglycerides, HbA1c, fasting plasma insulin, and homeostatic model assessment of insulin resistance [HOMA-IR])Regulation of extracellular matrix metabolism and bone biomineralization; participation in immune response, inflammation, and tissue repair [74,75,76,77][57][58][59Osteopontin participates in the regulation of bone mass through the neuron- and endocrine-mediated mechanisms ][60][55,56,57,58,59][38][39][40][41][42]
N-terminal propeptide of procollagen type 1 (P1NP) type 1 collagen (COL1) Osteoblasts, hepatic stellate cells N-terminal and C-terminal propeptides of procollagen type 1 represent the parts of the procollagen molecule. Procollagen type 1 is secreted into the extracellular space where the N-terminal and C-terminal propeptides are cleaved by propeptidases, generating the basic functional heterotrimeric unit of collagen 1. Collagen 1 contributes around 90% of the total organic component of bone matrix The dynamic and sensitive marker of changes in bone formation
N-terminal propeptide of procollagen type 1 (P1NP) Production of type 1 collagen during liver fibrosis increases up to 8-fold. The P1NP seems to be related to liver fibrosis development and progression in NAFLD and some other chronic liver diseases, such as primary biliary cholangitis, and alcoholic liver disease. Serum concentration of P1NP appears to be higher in patients with metabolic syndrome, compared to healthy subjects. At the same time, it was shown that elevated serum levels of P1NP were negatively correlated with triglyceride levels. [61,,83][78,44][79,6180,81,][62][63][64]82[65][60,61][43][44]
[66] Osteoprotegerin (OPG) TNF receptor superfamily member 11b (TNFRSF11B) Osteoblasts, medullary thymic epithelial cells, intestinal microfold cells, fibroblasts, vascular endothelial cells, and some cancer cells (e.g., breast and prostate cancers) Participation in bone homeostasis and regulation of calcium-phosphorus metabolism. It also plays a role in lymphnode organogenesis, immune modulation, fibrosis, angiogenesis, and vascular calcification. Currently the diagnostic, prognostic, and therapeutic value of osteoprotegerin in various cancers, especially bone metastasis, is widely discussed in the literature.
Osteoprotegerin (OPG) High serum osteoprotegerin levels are associated with liver fibrosis. Elevated serum osteoprotegerin levels were shown in patients with alcoholic liver fibrosis, primary biliary cholangitis, and viral cirrhosis compared to respective controls.

Osteoprotegerin may stimulate fibrogenesis in the liver through transforming growth factor beta 1 (TGFβ1) and is associated with the degree of fibrogenesis.		Osteoprotegerin is a negative regulator of bone resorption. It performs its function primarily through the impact on osteoclast development, activation, and apoptosis Serum levels of osteoprotegerin are increased in patients with metabolic syndrome. High serum levels of osteoprotegerin are associated with the poor control of type 2 diabetes mellites and the development of its complications. It was shown that osteoprotegerin levels were negatively correlated with body weight, waist circumference, HOMA-IR, and fasting plasma insulin, whereas they were positively correlated with insulin sensitivity. Taken together these data suggest that osteoprotegerin may serve as an independent predictor of metabolic syndrome. [62,84,85,86][45][67][68][69][62,63,,67][4564,][4665,][47][48]66[49][50]
Adiponectin Adiponectin, C1Q and collagen domain containing Exclusively adipose tissue, mainly visceral adipose tissue and to a lesser extent subcutaneous adipose tissue
AdiponectinFunctions as a homeostatic factor for regulating glucose levels, lipid metabolism, and insulin sensitivity through its anti-inflammatory, anti-fibrotic, and antioxidant effects Adiponectin has been demonstrated to have an anti-fibrotic action in the liver by blocking the activation of the expression of pro-fibrotic genes. Increased circulating adiponectin levels were found to be associated with the development of liver fibrosis. In contrast, both serum levels and hepatic adiponectin receptor expression were shown to be decreased in NAFLD. Adiponectin reduces the transport of fatty acids and the accumulation of triglycerides in the liver. Adiponectin induces an increase in circulating insulin levels, promotes the consumption of glucose by muscle cells and adipocytes, and inhibits the formation of glucose and glycogen in the liver and skeletal muscles. It also controls lipid metabolism by promoting the transport of fatty acids and β-oxidation in muscle cells by inhibiting hepatic lipogenesis and by stimulating the storage function of adipose tissue. [69,Adiponectin may have a pro-osteogenic role by stimulating osteoblast differentiation and activity, alongside inhibiting the osteoclastogenesis. 73,87][52][56][70][68,69,70,71,72,73][51][52][53][54][

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