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Hepatic de novo lipogenesis. Dietary carbohydrates, lipids, and proteins may be used as substrates for de novo lipogenesis. Carbohydrates are metabolized to three carbon intermediates dihydroxyacetone phosphate (DHAP) and glyceraldehyde three phosphate (GA3P) which are further metabolized to pyruvate. Pyruvate enters mitochondria to be used for energy production. When energy stores are plentiful, citrate is transported to cytoplasm where by the action of ATP citrate lyase (ACL) it is converted to acetyl-CoA. Acetyl-CoA carboxylase (ACC) converts acetyl-CoA to malonyl-CoA. Fatty acid synthase (FAS) sequentially adds acetyl-CoA to growing fatty acid chain to form saturated fatty acids, mainly palmitate. Palmitate may be further elongated to stearate or longer fatty acids by the action of elongation of very long-chain fatty acids (ELOVL6). Stearoyl-CoA desaturase 1 (SCD1) converts saturated fatty acids to monounsaturated fatty acids. Glycerol-3-phosphate acyltransferase (GPAT) adds acyl-CoA to glycerol-3 phosphate (G3P) to form lysophosphatidic acid (LPA). The enzymatic action of 1-acylglycerol-3-phosphate acyltransferase (AGPAT) adds second acyl-CoA to produce phosphatidic acid (PA), which is then dephosphorylated by lipin1 (LPIN1) to form 1,2-diacylglycerol (DAG). Diacylglycerol acyltransferase (DGAT) converts diacylglycerols into triglycerides (TG), which may be stored in the liver or assembled into VLDL and exported to circulate in the blood. Dietary lipids or adipocyte lipolysis supplies free fatty acids, which are converted in hepatocytes to acetyl-CoAs. They may be used in mitochondria for energy production or be exported back to cytosol as citrate and used for de novo lipogenesis similar to carbohydrates. Additionally, acetyl-CoA may be directly assembled into TGs by the action of DGAT bypassing the majority of enzymes involved in de novo lipogenesis. Proteins are degraded to amino acids, some of which may be used for gluconeogenesis and/or ketogenesis
Source publication
Nonalcoholic fatty liver disease (NAFLD) is a liver manifestation of metabolic syndrome. Overconsumption of high-fat diet (HFD) and increased intake of sugar-sweetened beverages are major risk factors for development of NAFLD. Today the most commonly consumed sugar is high fructose corn syrup. Hepatic lipids may be derived from dietary intake, este...
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Citations
... Accumulation of fat in the liver is directly associated with increased food intake. Dietary carbohydrates directly reach the liver via the hepatic portal vein, and excess intake is converted into fatty acids and stored as intrahepatic TAG (Softic et al., 2016;Tappy & Lê, 2012). Additionally, although ectopic fat accumulation has been observed in the liver of some overfed obese rats regardless of dietary composition (Fujita et al., 2018;Hwang et al., 2018;Tatsumi et al., 2011), fatty pancreas and intramuscular fat have been observed in high-fat diet-induced obesity models (Shin et al., 2021;Zhou et al., 2014). ...
This study examined the effects of exercise and detraining at a young age on fat accumulation in various organs. Four‐week‐old male Otsuka Long‐Evans Tokushima Fatty (OLETF) rats were assigned to either the non‐exercise sedentary (OLETF Sed) or exercise groups. The exercise group was subdivided into two groups: exercise between 4 and 12 weeks of age (OLETF Ex) and exercise between 4 and 6 weeks of age followed by non‐exercise between 6 and 12 weeks of age (OLETF DT). Body weight was significantly lower in the OLETF Ex group than in the OLETF Sed group at 12 weeks of age. Fat accumulation in the epididymal white adipose tissue, liver, and brown adipose tissue was suppressed in the OLETF Ex group. During the exercise period, body weight and food intake in the OLETF DT group were significantly lower than those in the OLETF Sed group. However, food intake was significantly higher in the OLETF DT group than in the OLETF Sed group after exercise cessation, resulting in extreme obesity with fatty liver and brown adipose tissue whitening. Detraining after early‐onset exercise promotes hyperphagia, causing extreme obesity. Overeating should be avoided during detraining periods in cases of exercise cessation at a young age.
... However, fructose metabolism differs from glucose metabolism in that it is not regulated by insulin. In mammals, fructose is often considered as the primary trigger for inducing non-alcoholic fatty liver disease due to its tendency to promote lipid synthesis [40,41]. Fructose has been demonstrated to facilitate triglycerides and lipid synthesis, as well as elevate the mRNA expression of the enzymes involved in glycolysis, lipogenesis, and gluconeogenesis [42,43]. ...
A 60 day feeding trial was conducted to evaluate the impacts of dietary carbohydrates with different complexities and configurations on the growth, plasma parameters, apparent digestibility, intestinal microbiota, glucose, and lipid metabolism of soft-shelled turtles (Pelodiscus sinensis). Four experimental diets were formulated by adding 170 g/kg glucose, fructose, α-starch, or cellulose, respectively. A total of 280 turtles (initial body weight 5.11 ± 0.21 g) were distributed into 28 tanks and were fed twice daily. The results showed that the best growth performance and apparent digestibility was observed in the α-starch group, followed by the glucose, fructose, and cellulose groups (p < 0.05). Monosaccharides (glucose and fructose) significantly enhanced the postprandial plasma glucose levels and hepatosomatic index compared to polysaccharides, due to the un-inhibited gluconeogenesis (p < 0.05). Starch significantly up-regulated the expression of the genes involved in glycolysis, pentose phosphate pathway, lipid anabolism and catabolism, and the transcriptional regulation factors of glycolipid metabolism (srebp and chrebp) (p < 0.05), resulting in higher plasma triglyceride levels and lipid contents in the liver and the whole body. The fructose group exhibited a lower lipid deposition compared with the glucose group, mainly by inhibiting the expression of srebp and chrebp. Cellulose enhanced the proportion of opportunistic pathogenic bacteria. In conclusion, P. sinensis utilized α-starch better than glucose, fructose, and cellulose.
... Fructose intake was recommended due to its low glycaemic index, however chronically high consumption of fructose, resulted to impaired insulin sensitivity in rodents (Bantle, 2006). Hepatic lipogenesis and lipotoxicity are believed to play a pivotal role in the metabolic effects of fructose on lipid metabolism (Softic et al. 2016). The consumption of fructose has been associated with increased hepatic lipogenesis, contributing to the synthesis of fatty acid within the liver. ...
... To address this, the role of carbohydrates, especially fructose, is gradually gaining recognition as being a determining factor in the development of MASLD and other metabolic diseases [6]. Fructose is a highly lipogenic sugar since its metabolism bypasses the rate-limiting step of glycolysis, and therefore activates de novo lipogenesis [7]. Fructose is also strongly associated with the progression and severity of MASLD [8,9]. ...
Metabolic dysfunction-associated steatotic liver disease (MASLD) is rapidly emerging as the most prevalent chronic liver disease, closely linked to the escalating rates of diabesity. The Western diet’s abundance of fat and fructose significantly contributes to MASLD, disrupting hepatic glucose metabolism. We previously demonstrated that a high-fat and high-fructose diet (HFHFD) led to increased body and liver weight compared to the low-fat diet (LFD) group, accompanied by glucose intolerance and liver abnormalities, indicating an intermediate state between fatty liver and liver fibrosis in the HFHFD group. Sirtuins are crucial epigenetic regulators associated with energy homeostasis and play a pivotal role in these hepatic dysregulations. Our investigation revealed that HFHFD significantly decreased Sirt1 and Sirt7 gene and protein expression levels, while other sirtuins remained unchanged. Additionally, glucose 6-phosphatase (G6Pase) gene expression was reduced in the HFHFD group, suggesting a potential pathway contributing to fibrosis progression. Chromatin immunoprecipitation analysis demonstrated a significant increase in histone H3 lysine 18 acetylation within the G6Pase promoter in HFHFD livers, potentially inhibiting G6Pase transcription. In summary, HFHFD may inhibit liver gluconeogenesis, potentially promoting liver fibrosis by regulating Sirt7 expression. This study offers an epigenetic perspective on the detrimental impact of fructose on MASLD progression.
... Other studies, evaluating the effect of fructose on NAFLD, have shown similar results [25,36,[42][43][44]. Fructose acts directly at the hepatic level, promotes lipogenesis, and leads to NAFLD characteristics [45]. In contrast, the other groups presented only mild steatosis except for the HFr-S5 group, which showed 10% moderate micro-and macrovacuolar steatosis (Table 3). ...
Spirulina (Arthrospira platensis) is reported to play a role in improving nonalcoholic fatty liver disease (NAFLD) and intestinal microbiota (IM). To study spirulina’s effects in the improvement of NAFLD characteristics, IM, and pancreatic–renal lesions induced by a fructose-enriched diet, 40 Wistar healthy male rats, weighing 200–250 g, were randomly divided into four groups of 10, and each rat per group was assigned a diet of equal quantities (20 g/day) for 18 weeks. The first control group (CT) was fed a standardized diet, the second group received a 40% fructose-enriched diet (HFr), and the third (HFr-S5) and fourth groups (HFr-S10) were assigned the same diet composition as the second group but enriched with 5% and 10% spirulina, respectively. At week 18, the HFr-S10 group maintained its level of serum triglycerides and had the lowest liver fat between the groups. At the phylae and family level, and for the same period, the HFr-S10 group had the lowest increase in the Firmicutes/Bacteroidetes ratio and the Ruminococcaceae and the highest fecal alpha diversity compared to all other groups (p < 0.05). These findings suggest that at a 10% concentration, spirulina could be used in nutritional intervention to improve IM, fatty liver, metabolic, and inflammatory parameters associated with NAFLD.
... A portion of ingested fructose is absorbed by gut epithelium, delivered to the liver via portal vein and phosphorylated in hepatocytes to be used in DNL. 19,20 This process may overwhelm hepatocytes by exhausting their energy supplies and lead to cellular stress. Once in the hepatocytes, fatty acids are either used to form triglycerides through esterification or undergo mitochondrial beta oxidation. ...
Background
The metabolically‐based liver disease, nonalcoholic fatty liver disease (NAFLD), is the most common cause of chronic liver disease currently affecting 38% of the world's adult population. NAFLD can be progressive leading to nonalcoholic steatohepatitis (NASH), liver transplantation, liver cancer, liver‐related mortality and is associated with decreased quality of life from impaired physical functioning and increased healthcare resource utilisation. However, screening for NAFLD is cost‐prohibitive but screening for high risk NAFLD (NAFLD with F2 fibrosis or greater) is imperative.
Aim
To review the global perspective on NAFLD and NASH
Methods
We retrieved articles from PubMed using search terms NAFLD, prevalence, clinical burden, economic burden and management strategies.
Results
NAFLD/NASH shows geographical variation across the globe. Highest prevalence rates are in South America and the Middle East and North Africa; lowest prevalence is in Africa. NAFLD's economic impact is from direct and indirect medical costs and loss in worker productivity. It is projected that, over the next two decades, the total cost of NAFLD and diabetes will exceed $1.5 trillion (USD). Risk stratification algorithms identifying “high risk NAFLD” were made following non‐invasive tests for NAFLD identification and fibrosis development. These algorithms should be used in primary care and endocrinology settings so timely and appropriate interventions (lifestyle and cardiometabolic risk factor management) can be initiated.
Conclusions
To reduce the burgeoning burden of NAFLD/NASH, management should include risk stratification algorithms for accurate identification of patients, linkage to appropriate settings, and initiation of effective treatment regimens.
... [21][22][23][24] Our group adopted the term HIVAMD to describe MD specifically on PLWH as it may have particular distinctive characteristics and contribution to the accelerated aging process. On the other hand the overconsumption of Ultra-processed foods (UPFs) , specially excess of Fructose, has also being linked to metabolic syndrome ,inflammation, microbial translocation , MD, and fatty liver , [25][26][27][28][29][30] hence, an unhealthy diet may also accelerate the aging process of PLWH and may be contributing to HIVAMD and weight gain. ...
Introduction
With the advent of antiretroviral therapy (ART), HIV has transitioned from a fatal disease to a chronic condition, enabling people living with HIV (PLWH) to achieve life expectancies similar to those of the general population. However, PLWH experience higher rates of non-AIDS-related illnesses, particularly metabolic diseases such as insulin resistance, fatty liver, and metabolic syndrome. These conditions, collectively referred to as “inflammaging,” are attributed to chronic inflammation and immune activation, but their underlying causes remain debated. This review explores the role of ultra-processed foods (UPFs) in exacerbating HIV-associated mitochondrial dysfunction (HIVAMD) and its impact on weight gain and metabolic complications.
Methods
The review examines existing literature on the impact of ART on metabolic health in PLWH, differentiating between lipohypertrophy and obesity. It investigates the proposed mechanisms linking ART to metabolic dysregulation, including the effects of UPFs, especially fructose, on mitochondrial function. Data on insulin resistance, hyperinsulinemia, microbial translocation, and the potential exacerbation of these conditions by UPFs are synthesized to propose a comprehensive model.
Results
ART, particularly integrase strand transfer inhibitors (INSTIs), has been associated with increased visceral adipose tissue (VAT) and metabolic syndrome. Proposed mechanisms include ART-induced alterations in appetite regulation, insulin signaling, and energy expenditure. HIVAMD is identified as a key factor in metabolic complications, with UPFs contributing to mitochondrial dysfunction, insulin resistance, and microbial translocation. Fructose overconsumption is highlighted for its role in liver inflammation, fatty liver, and metabolic syndrome through mechanisms such as ATP depletion, NAD+ depletion, and oxidative stress.
Conclusion
PLWH are at increased risk of metabolic complications due to the combined effects of HIVAMD and the consumption of UPFs. Addressing these issues requires prospective clinical trials to evaluate dietary interventions and nutritional supplements. Lifestyle modifications, such as intermittent fasting and pharmacological measures, may mitigate these complications. Community-based research initiatives are essential for developing and implementing effective interventions to improve the metabolic health of PLWH.
... Furthermore, SREBP-1 is a transcription factor that regulates the expression of genes responsible for lipid syntheses, such as acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) (reviewed in [90]). In turn, ACC mediates the conversion of acetyl-CoA to malonyl-CoA, and FAS converts malonyl-CoA into palmitate, which can be esterified to triacylglycerols and stored in the liver tissue (reviewed in [91]). ...
The literature offers a consensus on the association between exercise training (ET) protocols based on the adequate parameters of intensity and frequency, and several adaptive alterations in the liver. Indeed, regular ET can reverse glucose and lipid metabolism disorders, especially from aerobic modalities, which can decrease intrahepatic fat formation. In terms of molecular mechanisms, the regulation of hepatic fat formation would be directly related to the modulation of the mechanistic target of rapamycin (mTOR), which would be stimulated by insulin signaling and Akt activation, from the following three different primary signaling pathways: (I) growth factor, (II) energy/ATP-sensitive, and (III) amino acid-sensitive signaling pathways, respectively. Hyperactivation of the Akt/mTORC1 pathway induces lipogenesis by regulating the action of sterol regulatory element binding protein-1 (SREBP-1). Exercise training interventions have been associated with multiple metabolic and tissue benefits. However, it is worth highlighting that the mTOR signaling in the liver in response to exercise interventions remains unclear. Hepatic adaptive alterations seem to be most outstanding when sustained by chronic interventions or high-intensity exercise protocols.
... There will be a continuous decrease in ATP and phosphate [131][132][133][134] leading to an increase in uric acid, ATP deficiency [135], inhibition of protein synthesis, and increased oxidative stress [134,136]. Fructose is able to stimulate the DNL pathway while inhibiting β-oxidation through ChREBP and SREBP1c, and less FFA consumption [136,137]. These steps worsen steatosis (Figure 4). ...
The epidemiological burden of liver steatosis associated with metabolic diseases is continuously growing worldwide and in all age classes. This condition generates possible progression of liver damage (i.e., inflammation, fibrosis, cirrhosis, hepatocellular carcinoma) but also independently increases the risk of cardio-metabolic diseases and cancer. In recent years, the terminological evolution from “nonalcoholic fatty liver disease” (NAFLD) to “metabolic dysfunction-associated fatty liver disease” (MAFLD) and, finally, “metabolic dysfunction-associated steatotic liver disease” (MASLD) has been paralleled by increased knowledge of mechanisms linking local (i.e., hepatic) and systemic pathogenic pathways. As a consequence, the need for an appropriate classification of individual phenotypes has been oriented to the investigation of innovative therapeutic tools. Besides the well-known role for lifestyle change, a number of pharmacological approaches have been explored, ranging from antidiabetic drugs to agonists acting on the gut–liver axis and at a systemic level (mainly farnesoid X receptor (FXR) agonists, PPAR agonists, thyroid hormone receptor agonists), anti-fibrotic and anti-inflammatory agents. The intrinsically complex pathophysiological history of MASLD makes the selection of a single effective treatment a major challenge, so far. In this evolving scenario, the cooperation between different stakeholders (including subjects at risk, health professionals, and pharmaceutical industries) could significantly improve the management of disease and the implementation of primary and secondary prevention measures. The high healthcare burden associated with MASLD makes the search for new, effective, and safe drugs a major pressing need, together with an accurate characterization of individual phenotypes. Recent and promising advances indicate that we may soon enter the era of precise and personalized therapy for MASLD/MASH.
... Elevated de novo lipogenesis (DNL) is considered an important driver of MAFLD [5,9]. Hyperinsulinemia in metabolic syndrome leads to excessive hepatic DNL via activation of the LXR⍺-SREBP-1c cascade [66]. ...
Objectives
Compromised hepatic fatty acid oxidation (FAO) has been observed in human MASH patients and animal models of MASLD/MASH. It remains poorly understood how and when the hepatic FAO pathway is suppressed during the progression of MASLD towards MASH. Hepatic ChREBP⍺ is a classical lipogenic transcription factor that responds to the intake of dietary sugars.
Methods
We examined its role in regulating hepatocyte fatty acid oxidation (FAO) and the impact of hepatic Chrebpa deficiency on sensitivity to diet-induced MASLD/MASH in mice.
Results
We discovered that hepatocyte ChREBP⍺ is both necessary and sufficient to maintain FAO in a cell-autonomous manner independently of its DNA-binding activity. Supplementation of synthetic PPAR⍺/δ agonist is sufficient to restore FAO in Chrebp−/− primary mouse hepatocytes. Hepatic ChREBP⍺ was decreased in mouse models of diet-induced MAFSLD/MASH and in patients with MASH. Hepatocyte-specific Chrebp⍺ knockout impaired FAO, aggravated liver steatosis and inflammation, leading to early-onset fibrosis in response to diet-induced MASH. Conversely, liver overexpression of ChREBP⍺-WT or its non-lipogenic mutant enhanced FAO, reduced lipid deposition, and alleviated liver injury, inflammation, and fibrosis. RNA-seq analysis identified the CYP450 epoxygenase (CYP2C50) pathway of arachidonic acid metabolism as a novel target of ChREBP⍺. Over-expression of CYP2C50 partially restores hepatic FAO in primary hepatocytes with Chrebp⍺ deficiency and attenuates preexisting MASH in the livers of hepatocyte-specific Chrebp⍺-deleted mice.
Conclusions
Our findings support the protective role of hepatocyte ChREBPa against diet-induced MASLD/MASH in mouse models in part via promoting CYP2C50-driven FAO.
