Fructose

In 1900, the average fructose intake was 15 g/day which was consumed mainly through eating fruits and vegetables, which contain the added benefit of fiber. However, in 2010, fructose consumption had risen to 73 g/day consumed mainly in highly processed forms. PMID: 18769702.

Metabolism Pathway of Fructose & Glucose

Sucrose enzyme in the intestine breaks down Sucrose into Fructose and Glucose. 

In humans, glucose is easily absorbed via the (GLUT-2) protein and an active sodium/glucose cotransporter (SGLT) pump.PMID: 10926839 PMID: 6383475

In the Liver, glucose is broken down via glucokinase. Then it is Further broken down via phosphoglucose isomerase. Then it is Further broken down via phosphofructokinase which is the main rate-limiting step in glycolysis.

The liver is the primary location for fructose metabolism. The liver can extract (metabolize) around 40–70% of fructose dietary intake in both rats and humans, (PMID: 13110753 PMID: 34203484) while the remaining is metabolized by other tissues, since the liver is the main source of GLUT-5 (PMID: 3202090).

Anatomically, the liver is the first organ to receive absorbed nutrients via the portal vein; in that way(PMID: 651653). 

Dietary fructose exists in three forms: (1) the monosaccharide, (2) sucrose, a disaccharide of fructose and glucose, and (3) in chains as fructans.

Fructose has a lower glycemic response, which has been attributed to its slow rate of absorption

Fructose enters the portal venous system from the stomach [intestinal epithelial cells via the GLUT-5 protein transporter in humans PMID: 1634504] (PMID: 31905727), where it is carried to the liver and pancreas, and then a very small amount transported to other organs such as the brain, skeletal muscle, and heart through GLUT5, The main fructose transporter.GLUT5, It is expressed on adipose tissue, also expressed in skeletal muscle, (PMID: 9781312)  testis, kidney, and brain. ( PMID: 18398011)

In rats, fructose was injected rather than orally given, allowing it to bypass the hepatic absorption process and reach to brain in a minimal amount, where it was used as an energy source (Hypothalamic region)PMID: 10480611

Fructose is rapidly broken down via fructokinase. Then it is further broken down via aldolase B. Then it is further broken down via trio kinase, until this point in fructose metabolism, there have been no rate-limiting steps; hence it can lead to different metabolic pathways like glycolysis, glycogenesis, gluconeogenesis, Lipogenesis, and fatty acid esterification. After the 3rd stage, it is further broken down to pyruvate via the rate-limiting enzyme, pyruvate kinase, thus leads to an increased flux of pyruvate into the Krebs’s cycle.

In the Liver, Fructose overflow pyruvate. Pyruvate enters the mitochondria and forms acetyl coenzyme, also known as Acetyl-CoA.Acetyl-CoA acts as a carbon source for three different pathways: the citric acid cycle also known as Krebs’s cycle, Lipogenesis, and the formation of ketone bodies. In the lipogenic pathways, acetyl-CoA acts helps for the production of long-chain fatty acids. Fatty acid synthase is a multienzyme complex that helps facilitate the conversion of acetyl-CoA to long-chain fatty acids.

There are multiple mechanisms to explain why fructose might be more problematic compared to the consumption of an equivalent amount of glucose. Trigger hepatic and systemic inflammation via increased intestinal permeability and the translocation of endotoxin from the gut and into the circulation.PMID: 18395289Rat

Increase in de novo Lipogenesis (liquid fructose in place of solid carbohydrate foods), which can increase production of fetuin-A,  (a glycoprotein secreted by the liver and adipose tissue) leading to increased activity of inflammatory pathways in adipose tissue.

TRANSCRIPTION FACTOR: Fructose increases liver expression of SREBP-1 (sterol regulatory element-binding protein) and ChREBP family proteins; the lipogenic enzymes responsible for triglyceride synthesis.PMID: 11994399 PMID: 15118080 PMID: 11567032

PPAR: PPAR-α is a liver transcription factor that enhances fatty acid beta-oxidation. Fructose directly suppresses PPAR-α, which leads to less fatty acid oxidation and thus promotes hypertriglyceridemia.PGC-1β is a direct coactivator for SREBP-1c.PPAR-γ regulates Lipogenesis via SREBP-1c.

Fructose increases levels of the proinflammatory transcription factor, nuclear factor-kappa-B (NF-κB).PMID: 17326204

Fructose can stimulate FOXO1 expression,FOXO1 promotes the hepatic production of Apolipoprotein- 3 ApoC3, a strong lipoprotein lipase (LPL) inhibitor.PMID: 15546000 Comparative Thus, it appears that fructose is a dual threat to plasma triglyceride clearance through its ability to activate ApoC-III and its inability to produce significant insulin release.

NOTE: Differences in gene expression could be attributed to several factors, such as overeating, novelty, and differences in sensory and reward factors that accompany sugar intake.

ENZYMES REACTION : 11β-HSD1 and G6PD enzymes have been linked to obesity, in particular to omental obesity in both humans and animal models. The rats given 24-h dilute fructose solutions dramatically increased hepatic 11β-HSD1 and G6PD, whereas had no effect on either enzyme provided access to the same concentration of glucose.7-day access to sucrose had a comparable effect on hepatic 11β-HSD1. Again, 7-day access to glucose failed to induce any significant effect on either enzyme, despite comparable sugar intake in both sucrose- and fructose-fed rats. Sugars can influence the regulation and/or expression of these enzymes.PMID: 21127473

HORMONES: Cholecystokinin was reduced drastically in fructose-fed rats.

Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator of the leptin and insulin signaling pathways.PMID: 23374726 REVIEW 

Chronic fructose feeding causes PTP-1B overexpression in hamsters and mice, PMID: 11598116 PMID: 15561934. In that way, fructose promotes increased VLDL synthesis and release.

The human small intestine has a limited ability to absorb fructose, compared with the ability to absorb glucose rapidly and completely.PMID: 17625977

Researchers have targeted high-fructose corn syrup (HFCS) as a potential factor contributing to the obesity epidemic PMID: 24830053 REVIEW  PMID: 20219526 RAT  PMID: 22289979 observational  PMID: 22034869 REVIEW

In 1960, HFCS appeared due to an easier, cheaper and abundant process derived from corn whereas Sucrose from sugarcane is difficult, costly and unstable due to its physical properties and Climate. PMID: 19064536

100% Glucose, which is corn syrup, is extracted from corn starch and enzymes are added to it for fructose conversion. 
Despite the name “high-fructose,” HFCS actually has approximately the same amount of fructose and glucose as sucrose or honey.PMID: 19064536
Fructose is “toxic” and should be “treated as alcohol” PMID: 20800122  PMID: 22297952 animal studies.
No evidence that fructose, when consumed in realistic amounts (≤ 100g/day), is particularly harmful PMID: 24666553 PMID: 21050460
Studies comparing intake of sucrose, HFCS, and other similar sweeteners such as honey have found they exert similar metabolic effects, and that HFCS does not uniquely contribute to weight gain PMID: 22866961 PMID: 19064539 PMID: 26338891

Correlation ≠ Causation

HFCS consumption increased sharply after 20th century, which correlate with obesity rates in the U.S. PMID: 25471927 on the other hand  total calorie intake also increased dramatically in the U.S. from 1970-2000 .

Obesity is a multifactorial problem.

HFCS is a sweetener found in processed foods, and processed foods tend to be less nutrient dense and more calorically dense than unprocessed foods, HFCS is harmless, and need not be feared.

In the gaining Phase, the fructose you eat is much more likely to be converted to fat.

Fructose consumption might be more beneficial in deficit, but is it wise to eat simple carbohydrates compared to complex carbohydrates because complex can regulate blood glucose more efficiently than simple one. Moreover, it will help to combat hunger in the deficit phase. But what about nutrients density, other polyphenols & antioxidants which we can get from fruits which can be more beneficial than complex one?

Our body cells doesn't use fructose as an energy source, cells use glucose or ketones.

First, if our body cells apart from fiber can't use fructose, then why we have GLUT5 on cells of other part of the body. Cells can use fructose but in small quantity.

Second, Fructose can get converted to glucose other than fat depends on body energy status and the body can utilize glucose as an energy source.

Fructose is similar to Ethanol or alcohol, so the body treats it like an alcohol; hence it's toxic.

Just because alcohol doesn't get metabolize apart from the liver doesn't make fructose toxic.

Alcohol has other health consequences which fructose doesn't have.

Fruits are seasonal and regional; hence nature has not given in excess, but due to technology, it's available every time everywhere.

Eating fruits with their session is still acceptable.

A 2011 Review Study, Fructose malabsorption issue, In practice, diarrhea and other symptoms will develop only if fructose is consumed in (unnaturally) big amounts and in the absence of glucose.
When fructose is ingested with glucose at about similar or even greater levels of glucose, even those who suffer diarrhea from fructose eating in big quantities will normally have no issue digesting it.PMID: 21793722

A 1983 Single-blinded Study (16 healthy Adults,8 men & 8 women, Age 23 to 48 yrs, no history of recent or recurrent gastrointestinal symptoms, malabsorption symptoms, recent antibiotic use, or diagnosis of gastrointestinal disease, No awareness of dietary intolerance to fruit,50g Fructose in water:20% Solution 50g,37.5g,25g:10%Solution 50g Sucrose:10% Solution).
50 g Fructose: 10% solution, was incompletely absorbed in 6 of 16 subjects. 
50 g Fructose: 20% solution resulted in an increased frequency of incomplete absorption in 10 of 14 subjects.
37.5 g Fructose:  10% solution lowered the frequency of incomplete absorption to 2 of 14 subjects.
25 g fructose:  10% solution was absorbed by the 3 of 14 subjects.
50 g sucrose, 15 adults, absorbed it entirely.
Incomplete absorption was associated with symptoms of cramps or diarrhea, or both, in 5 of these 6 individuals. PMID: 6847852

NOTE: Solution was used, not fruit, to study about High Fructose Corn Syrup.

• Absorption of fructose is improved when it is ingested with glucose (such as in sucrose) because glucose absorption stimulates pathways for fructose absorption.PMID: 28358334
• Breath hydrogen testing has revealed that up to 75% of healthy people will incompletely absorb a large quantity of fructose (50 g) taken alone.PMID: 25298621

Incomplete intestinal absorption of fructose.

D-Fructose is one of the three dietary monosaccharides, along with glucose and galactose, found in fruits. L-fructose does not occur naturally and can be produced synthetically also called as unnatural L-sugars, such as the non-nutritive sweetener L-fructose.

Is l- Fructose bad for your health?

Yes, Fructose can also be used by other organs, and three specialized enzymes, ketohexokinase (KHK, fructokinase), aldolase B, and trio kinase, are responsible for fructose metabolism in the liver(Reference). KHK-A is also expressed in the pancreas, intestine, brain, lung, eye, adipose, spleen, skeletal muscle, heart, uterus, and the adrenals.(PMID: 19365088)

No, Fructose stimulates only modest insulin secretion due to GLUT 5 low levels of expression in pancreatic β-cells (PMID: 9004533) hence for transportation & metabolism; hence  fructose does not require the presence of insulin to enter cells either it leptin(Reference,PMID: 15723702).

Hypothesize that the leptin reduction observed during prolonged consumption of diets high in fructose may lead to increased energy intake and/or decreased energy expenditure and weight gain

Insulin increases leptin release and fructose does not stimulate insulin; hence  fructose ingestion might inhibit appetite less than consumption of other carbohydrates and lead to increased energy intake.

In a study of 28 obese men, beverages containing 50 g WPI, fructose, or glucose or 25g whey plus 25 g fructose had similar effects on appetite (p>0.05)PMID: 17593904.

Leptin production drops by 20–30% when subjects consumed fructose-sweetened beverages (30% of caloric intake) compared to glucose-sweetened beverages.PMID: 15181085 HUMAN CLINICAL TRIAL  PMID: 19208729 RCT 

Sugary foods motivate intake despite satiety (PMID: 19726714)

Sucrose can induce addiction-like behaviors such as bingeing and dependence (PMID: 15642609 RAT   PMID: 16669597 ANIMAL PMID: 17924782 ANIMAL ).

Sucrose bingeing decreased D2 receptors (Dopamine D2-autoreceptors plays a key role in regulating the activity of dopamine neurons and controls the synthesis, release, and uptake of dopamine.) and μ-opioid receptors in rats; this effect is similar to that seen with morphine(PMID: 15135221). These data clarify it that sugar (either sucrose or fructose) can have a major impact on reward and possibly addiction, as both phenomena are mediated by dopaminergic pathways.

In rhesus monkeys, the consumption of fructose over 3- and 6-month periods resulted in significant weight gain and decreased energy expenditure.PMID: 21884510

High-fructose consumption may have an effect on central appetite regulation by influencing specific components of the endocannabinoid system.PMID: 25988134

In January 1966  Esko Nikkila and Kaarina Ojala  Ojala (Department of Medical Chemistry, Finland) were among the first to report that fructose consumption leads to a dramatic increase in circulating triglycerides.

Mechanically, fructose is uniquely and quickly converted from sugar to circulating fat, prompting hypertriglyceridemia.PMID: 8432416 RAT STUDY  PMID: 7047694 RAT STUDY  PMID: 4295617 RAT STUDY.

Mechanistically, Liver fructose metabolism generates precursors (Cofactor Or pathways Or materials) for gluconeogenesis, de novo Lipogenesis(DNL)(PMID: 28878197), dyslipidemia, hepatic lipid droplet formation, and steatosis (fatty liver) due to inadequate clearance of lipid produced during fructose metabolism. 

Dietary fructose increases levels of enzymes involved in liver de novo Lipogenesis (DNL) even more strongly than the High Fat Diet. Several properties of fructose metabolism make it particularly lipogenic. Fructose increases protein levels of all DNL enzymes during its conversion into triglycerides. Fructose also leads to ATP depletion and suppression of mitochondrial fatty acid oxidation, resulting in increased production of reactive oxygen species. (PMID: 26856717 2016 review )

Fruit is not a calorie-dense food, since most fruits are low in fat. Fruit is basically a package of water and fiber with small amounts of other nutrients. The Fruit contains vitamin C, also known as ascorbic acid, which aids in the production of catecholamines like norepinephrine, which promote in the release of fat stored in fat cells for use as energy.
Studies show that obese people tend to show lower levels of nutrients that are rich in fruits, such as vitamins C, A.A shortage of essential nutrients contributes to the leptin resistance that is seen in many obese people.
The nutrients found in fruit can down regulate genes known to promote obesity through increased appetite and other pathways.

Phytochemical/Phytonutrients

The term “phyto” indicates that the substance is sourced from plants. Phytonutrients only exist in plants such as resveratrol, caffeic acid, naringenin, proanthocyanidins, catechins, and cyanidin, they often serve as protective factors to prevent the negative effects of ultraviolet rays from the sun, or to ward off predators. 

Phytochemicals appear to offer potent antioxidant effect that aids fat loss;suppression of the formation of fat new cells; Inhibiting the differentiation of cells that can become fat cells; blocking the synthesis of fat in fat cells; and promoting the self-destruction of fat cells PMID: 22254051 also protects against the diseases including cancer, cardiovascular disease, type-2 diabetes.

Resveratrol: Animal studies reveal that it has significant antioxidant function and can interact with genes in the human body to the point that it may provide some protection against disease.
There is a lot of information on resveratrol in the medical literature.
The beneficial effects of resveratrol largely found in animal, rather than human, Studies.
Human studies on resveratrol are paradoxical (some show benefits, whereas others show nothing) because resveratrol is rapidly metabolized in the liver 14 minutes after oral ingestion. The liver converts resveratrol into metabolites, the majority of resveratrol metabolites seem to be excreted in the urine.

Naringenin:It appears to provide some potent effects in helping to mobilize and oxidize body fat. It activates genes that provide an increased metabolic effect with caffeine, naringenin extends the activity of caffeine, including the fat mobilizing properties of caffeine.

Pterostilbene: Pterostilbene is similar to resveratrol in that its bioavailability is around 20% for orally taken resveratrol and 80% for pterostilbene.

In a 12-week study using Pterostilbene supplementation, 67% of pre-diabetic individuals had normal blood glucose levels. However, the glucose-lowering benefits of pterostilbene occur at extremely high doses of 250 mg or more, but lesser doses are known to have a significant antianxiety impact.

PQQ:PQQ stimulates the production and release of a chemical known as PGC1-a, which in turn promotes the formation of new mitochondria in cells. More mitochondria indicate high muscle endurance. As ATP and lipids are oxidized, more energy is produced.

Intestinal Microbiota: The strains of gut bacteria must be balanced. Too much of one kind can adversely affect appetite, causing fat gain, or it can enhance fast oxidation of carbohydrates and fat, preventing fat gain.
Intestinal bacterial activity influences immune response as well as the way the body consumes and absorbs nutrients, mainly fat and carbohydrates.
Because of the naturally occurring high soluble fibre, which works as a fuel and food supply for the gut bacteria, fruit may promote fat reduction via beneficial effects on the intestinal microbiota.
The intestinal bacteria digest soluble fibre like 'inulin,' producing short-chain fatty acids like acetate and propionate, which react with free fatty acid receptor-2. This increases a Peptide YY in the colon by 130%, which goes to the brain and suppresses hunger by 33% or more. Peptide YY is a protein that suppresses hunger.
Lean persons have more Bacteroidetes and Actinobacteria strains of bacteria, which are connected to lower calorie uptake, whereas those with more body fat have more Firmicutes and Proteobacteria, which are linked to higher calorie and carbohydrate uptake. The fruit's soluble fibre promotes “lean bacteria” growth.

Phenols in blueberries appear to slow the loss of neurons in the brain, reverse age-related defects in motor function.
Each fruit contained large levels of different phenolic compounds. Scientists believe that unknown nutritional ingredients in fruit can impact both health and body composition.
One crucial element of phytochemicals is that none are necessary in the human nutrition. There is currently no known deficiency disease associated with their absence in the human nutrition.

A 2020 Cohort Study (10 healthy Adults,5 Adults with NAFLD, Age: 28 ± 19 yrs, normal glucose tolerance, Hyperinsulinemic euglycemic clamp,150 g each daily fructose)High-fructose consumption with steady calorie intake had no effect on body weight, skeletal muscle insulin sensitivity, liver and skeletal muscle lipid, postprandial plasma glucose and triglycerides.PMID: 31796953

Final Thoughts 

Avoiding the consumption of any fruit while on a diet is because they are rich in fructose. The general belief is that because fruits are rich in fructose, they promote fat gains in the body, or slow down the loss of fat when dieting. This is based on some keyword  “excessive” consume of fructose leads to fat gain, fatty liver, diabetic or an increase in uric acid.

But several factors are missed in making claims.

Let's take a closer look at each of these factors one by one.

1. Fruits do contain fructose, it is the natural, unprocessed form of the sugar, not the highly processed type.
2. Fruits include not just fructose but also fibre, which has been shown to lower body fat, manage blood glucose, and have other metabolic health benefits. Fruits which contain more fructose and glucose have higher fiber content, Eg:sugarcane.
3. Fruits, in addition to fructose, provide a variety of additional nutrients that have been linked to improved blood glucose control and other health advantages.
4. As a result of factors 2 and 3, fruits have a low glycemic load despite having a high glycemic index.
5. you would need to eat a lot of fruit to ingest a significant amount of fructose.

There are Food which build up fat in the liver on other hand, there are drinks like green tea which reduces fat formation in the liver.

No
Insulin Resistance:Higher the insulin level goes less leptin level, hence over consumption happens of food brain sees less leptin level and hence the brain is still starving. Leptin turns off the appetite signal, but it doesn't.Hyperinsulinemia stops the leptin from acting on the nucleus accumbens; hence appetite is not regulated, which leads to more food.

Glucose and fructose have similar metabolic fates because most of the dietary fructose converts into glucose.(PMID: 23031075)
While there is evidence that carbohydrates have a role in the diabetes epidemic, much of the available data comes from low-quality observational research, animal models, and overfeeding trials with high-intake levels. Prospective cohort studies have found no consistent link between fructose-containing carbs and weight gain or diabetes risk. Although there are strong links between the highest and lowest levels of sugar-sweetened beverages consumption, these links are small, do not hold at different levels of intake, and are sensitive to correlated effects.(PMID: 29872464)

In 2018, The American Diabetes Association (ADA) advises that people with or at risk for diabetes avoid sugar - sweetened beverages (soft drinks, fruit drinks, energy, and vitamin type water drinks containing sucrose, high-fructose corn syrup, and/or fruit juice concentrates). This is to reduce the risk of worsening the cardio metabolic risk profile and to prevent weight gain.

In 2009, A Scientific Statement From the American Heart Association, New evidence on the relationship between intake of sugars and cardiovascular health has emerged since the last American Heart Association (AHA) scientific statement was published in 2002.

In 2016, A Scientific Statement From the American Heart Association Strong evidence supports the association of added sugars with increased cardiovascular disease risk in children through increased energy intake, increased adiposity, and dyslipidemia.

A diet high in fructose can produce adverse metabolic changes such as increased plasma triglycerides, hepatic insulin resistance, and hepatic steatosis (PMID: 20471804).

Fructose may increase visceral fat more than glucose. One difference between glucose and fructose may be that the latter reduces leptin (the “satiety hormone”).

In vivo, chronic fructose intake promotes white adipose tissue accumulation through activating adipogenesis. In vitro, fructose alone induces adipogenesis by several mechanisms, including triglycerides and very-low-density lipoprotein (VLDL) production by fructose metabolism, The stimulation of glucocorticoid.

Moreover, fructose induces adipogenesis through the inhibition of the thermogenic program by regulating Sirt1 and UCP1. 

Finally, microRNAs (MicroRNAs are small, highly conserved non-coding RNA molecules involved in the regulation of gene expression)  may also be involved in regulating adipogenesis in high fructose intake conditions.PMID: 31181590 

Fructose also contributes to muscle insulin resistance and activates mitogen-activated protein kinase/c-Jun N-terminal kinase (JNK-1) (JNK (c-Jun N-terminal kinase) is a member of the MAPK (mitogen-activated protein kinase) family that regulates a range of biological processes., both of which are linked to hepatic insulin resistance. Hepatic insulin resistance promotes Hyperinsulinemia and encourages metabolites to deposit into fat.

The promotion of reactive oxygen species (ROS) production through uric acid (causes substrate-dependent phosphate depletion), NOX (NADPH oxidase) and XOR (Xanthine oxidase is a form of xanthine oxidoreductase, a type of enzyme that generates reactive oxygen species). This can further catalyze of xanthine to uric acid) expression. In addition, fruits are rich in antioxidants.
mTORC1(mammalian target of rapamycin complex 1)  signaling and Ang II initiation (Angiotensin is a peptide hormone that causes vasoconstriction and an increase in blood pressure. It is part of the renin–angiotensin system, which regulates blood pressure. Angiotensin also stimulates the release of aldosterone from the adrenal cortex to promote sodium retention by the kidneys).

Fructose metabolism contributes can reduce acetylcholine-mediated arterial dilation by reducing the bioavailability of endothelial nitric oxide synthase levels and reducing nitric oxide (NO) again contributing to elevated blood pressure (hypertension).PMID: 19321578 

In contrast to ingestion of glucose, an oral fructose load increases FGF21(Fibroblast growth factor 21 is a liver-secreted peptide hormone in response to nutritional stresses, its exact physiological role is unknown!) levels acutely within 2h.PMID: 25685689

However, chronic fructose feeding for 12 weeks did not change FGF21 levels significantly despite an increase in liver fat, fasting and postprandial triglycerides, and insulin resistance.PMID: 28548281

Age-related changes in fructose intake capability are not explained by the rate of expression of GLUT 5. PMID: 18398011 PMID: 15362482 RAT STUDY PMID: 15542355 RAT STUDY )

GLUT 5 depletion was more severe in fat cells from obese mice, which developed more severe insulin resistance.(PMID: 15362482)

Fruits contain very less Fructose per 100gm.100gm is a huge quantity.
Fruits contain fiber & other nutrients which help in sensitizing insulin due to which fruits hit in a different way than isolated Fructose.

GLUT5 expression levels and fructose uptake rates are also significantly affected by diabetes, hypertension, obesity, and inflammation and seem to be caused during carcinogenesis, particularly in the mammary glands.(PMID: 18398011)

NO, hypothesis:fructose consumption can disrupt normal liver metabolism, leading to increased liver Lipogenesis PMID: 15971409 REVIEW

11β-HSD1 (a regulator of intracellular glucocorticoids) was increased in the livers of rats after 24-h of fructose access.PMID: 21127473
Oxysterols receptor LXR beta and alpha (or liver X receptors β and α) are nuclear receptors that help regulate carbohydrate and lipid metabolism, which decrease and increase, respectively, in response to chronic fructose consumption.
The study found Significantly higher liver fat content in BPA-exposed rats than in fructose controls. BPA in combination with fructose appears to induce Fatty Liver at doses close to the current tolerable daily intake.PMID: 23142792

A small number of intervention studies shows that increasing the quantity of calories in the form of fat, sugar, or both increases liver fat storage. However, a hypocaloric diet lowers liver fat storage, suggesting that fatty liver is not associated with specific macronutrients.PMID: 28947639
Overweight males on a high-fructose or high-glucose diet had no significant changes in liver Lipid concentrations or blood levels of liver enzymes over the isocaloric period. During the hypercaloric phase, however, both high-fructose and high-glucose diets showed considerable increases in these parameters with no significant difference between the two groups.PMID: 23872500 RCT-DB

On hypercaloric diets, both fructose and glucose raised fasting VLDL, triglycerides, and liver glucose output but had no effect on fasting glucose, insulin, or ALT concentrations.PMID: 19930762 RCT - CROSSOVER

On hyperenergetic diets, both very high fructose and glucose reduce insulin sensitivity. Triglycerides rise in fructose, but there are no changes in liver fat, visceral fat, subcutaneous abdominal fat, or intramyocellular lipids. PMID: 21396140 RCT- SB

A 2014 Systematic Review and Meta-analysis of Controlled Feeding Trials showed,In healthy people, isocaloric (Nutrition energy balance) exchange of fructose for other carbs does not cause NAFLD symptoms.PMID: 24569542

Coming soon

Fructose does not stimulate insulin, hence fructokinase has to metabolize in to fructose 1-phosphate. In this process, ATP loses one phosphate which becomes ADP and ADP loses one phosphate which becomes AMP and then AMP loses one phosphate which becomes IMP and finally waste product uric acid. This process has to get over again and again because the majority of the fructose has to get metabolized by the liver through this pathway in which a lot of phosphate will get used; hence this is a volume issue.

Fructose raises uric acid levels, and uric acid inhibits nitric oxide bioavailability (uric acid blocks the enzymes in blood vessels known as endothelial nitric oxide synthase & these enzymes make Nitric oxide).

Elevated uric acid level, on a modern high-fructose diet, with sleep deprivation and insufficient physical activity PMID: 16219650.PMID: 16932373 PMID: 29433580 

Increase level of uric acid leads to GOUT.

A 2008 12 Years Prospective Cohort Study shows that consumption of sugar - sweetened soft drinks and fructose is strongly associated with an increased risk of gout  & may fructose rich fruits and fruit juices may also in men. Diet soft drinks were not associated with the risk of gout.PMID: 18244959

Final Thoughts 
The Mechanism Shows Excess fructose consumption can raise uric acid levels via an uncontrolled fructokinase pathway in the liver, which utilizes a lot of ATP to convert fructose to fructose-1-phosphate. Net ATP breakdown results in a buildup of AMP, which is then converted to uric acid. Furthermore, fructose can stimulate de novo purine synthesis, which results in the production of uric acid.

Fructose increases uric acid and uric acid decreases Nitric oxide and Nitric oxide reduces blood pressure; hence less Nitric oxide means imbalance in blood pressure which may lead to hypertension.

A meta-analysis of three prospective studies found no link between fructose and early hypertension; however, these studies used self-reports of doctor-diagnosed hypertension and did not consider current salt use.(PMID: 25144126 2014 REVIEW)

Another meta-analysis, cohort (n = 240,508) that includes data from the Coronary Artery Risk Development in Young Adults) and referenced by the American Heart Association update on the increased risk of hypertension with consumption of sugar sweetened beverages when sex, age, race, BMI, and smoking habits were controlled for.(PMID: 26269365 2015,PMID: 29386200 2018)

The risk of hypertension related to fructose in combination with greater salt consumption has not yet been studied in people, however the impact of combined intake has been studied in preclinical investigations.

Mechanism:

Renal apical (apex) chloride-base exchangers are essential to electrolyte and acid-base homeostasis.

There are transporters that are up-regulated by fructose in the small intestine and proximal renal tubule. The absorption of salt (sodium and chloride) in the small intestine is predominantly mediated via the chloride/base exchangers DRA (Down Regulated in Adenoma) and PAT1 (Putative Anion Transporter 1), and the Na(+) /H(+) exchanger NHE3 (Sodium Hydrogen Exchanger 3). PAT1 and NHE3 also co-localize on the kidney proximal tubule.PMID: 21143427

Increased dietary fructose intake for several weeks unregulated the expression of NHE3, PAT1 and Glut5 in the intestine and resulted in hypertension.(PMID: 21143427 MICE STUDY)

Increased dietary fructose intake (60% fructose) for 2 weeks enhanced the mRNA expression and protein abundance of Glut5, PAT1 and NHE3 in jejunum vs. control diet (60% starch). Also, a high fructose diet significantly decreased the daily excretion of chloride and sodium in the kidney.(PMID: 18496516 RATS STUDY)

Glut5+/+ mice showed a sixfold increase in their blood fructose levels whereas Glut5-/- deletion mice develop hypotension after 5 days of increased dietary fructose intake, as a result of volume depletion. This indicates that the presence of Glut5 is essential for the fructose-stimulated salt absorption in the intestine and plays a fundamental role in the generation of fructose.PMID: 19091748

Sodium absorption occurs throughout the small intestine via the putative anion transporter 1 (PAT1), which increases with fructose intake in both the jejunum (PMID: 18496516,PMID: 11842009)and kidney.(PMID: 21789281)

PAT1 also co-localizes with GLUT5, a glucose transporter with a low affinity for glucose and a high affinity for fructose.

Fructose sensitizes the proximal tubule to angiotensin II (PMID: 24379189)

High salt intake in rats on 20% fructose, but not glucose, resulted in a 41% increase in RSNA( renal sympathetic nerve activity) after 1 week.PMID: 29847164

A 2015 Prospective, Blinded, RCT,10 weeks Study (Both participants and staff members were blinded, weight maintenance calories,267 men and women, the ages of 20 and 60 years, weight-stable, normal blood pressure <140/90 mm Hg individuals, BP and uric acid measurements were checked before and after 10 weeks, drank sugar-sweetened 1% fat milk every day for 10 weeks with mixed-nutrient diet (high-fructose corn syrup, fructose, glucose, and sucrose), Groups 1 and 2 had 9% estimated caloric intake from fructose or glucose, respectively, Groups 3 and 4 had 18% of estimated caloric intake from high fructose corn syrup or sucrose, respectively)
Showed At the end of the 10 weeks there was a significant reduction in both systolic and diastolic BP with no change in uric acid levels despite an average 2-pound weight gain.Energy intake increased by 12.1%, with increased protein intake but decreased fat intake.PMID: 25496265

Coming soon

In One double-blind, crossover-controlled, randomized clinical trial study, Fructose has lower net whole-body glycogen storage and lower performance during future exercise than glucose; a solution containing fructose reduces thermoregulatory responses when compared to glucose.PMID: 28100512

Some study indicates the dosage where fructose starts to get primarily converted to fat is around 60 -100 grams per day on average. PMID: 18996880 PMID: 19592634 None of this study included was on hard-training bodybuilders which have different blood and body composition compared to sedentary population, which means the dosage could be higher for people who train and follow nutrition. 

Recent research suggests that compared with water, a solution containing fructose attenuates thermoregulatory responses compared with glucose (PMID: 24300126)

In comparison to a High Glycemic Index meal (group 1 spaghetti and group 2 glucose and rice), 26gms fructose in a Low Glycemic Index breakfast reduced postprandial and exercise fatty acid oxidation by -21% during following brisk walking.(PMID: 22081046). Cons: Two methodologically flawless 1) different foods are used in meal among groups 2) used fructose in powdered form instead of whole fruit (SuppVersity)

A 2016 Study Showed Sucrose Ingestion After Exhaustive Exercise Accelerates Liver, but Not Muscle Glycogen Repletion Compared With Glucose Ingestion in Trained Athletes.PMID: 27013608

Coming Soon

Hereditary fructose intolerance (HFI) A mutation in the gene encoding aldolase B enzyme impairs the breakdown activity of the enzyme and prevents fructose from being converted to glucose.
The genetic mutation (genotype) is permanent, the phenotype is not. 
Hence, eliminating specific foods and food ingredients essentially keeps the disease silent.

Ethanol is metabolized primarily in the liver by alcohol dehydrogenase. This results in acetaldehyde production, Acetaldehyde is a toxic byproduct of alcohol metabolism that causes damage to mitochondrial membrane structure and function.

Coming soon

YES
A 2001 Clinical Trial, single blind randomized (11 healthy Adults,5 men & 6 women,75 g glucose with or without 7.5 g fructose,2 African-American,3 Asian,6 Caucasian, age 29 ± 2 yrs, Hemoglobin A1c ranged 4.5–6.4% (normal, 4–6.5%), no medications, normal blood counts, serum electrolytes, liver, renal function, No diabetes, consumed 200 g carbohydrate daily, glucose oxidase technique using Glucose Analyzer II, Plasma insulin & glucagon measured by RIA, Lactate & fructose measured in blood deproteinized with perchloric acid)
Showed Low does fructose improve the glycemic response to an oral glucose load in normal adults without significantly enhancing the insulin or triglyceride response.
Note:Glucose tolerance was improved by fructose in 9 subjects and worsened in 2.PMID: 11134101

A 2001 Clinical Trial, single-blind randomized Study (5 obese Adults, type 2 diabetes,1 man & 4 women,1 African-American and 4 Caucasians, aged 42 ± 5 years, All subjects consumed 200 g carbohydrate daily for 1 week before study,7.5 g fructose in addition to the 75 g glucose)
Showed In type II diabetic subjects, 7.5g of additional fructose reduces glycemia in response to 75g of glucose by 14%. For a Marathon runner, high fructose corn syrup can replenish liver glycogen faster than with glucose alone. PMID: 11679451

“The dose makes the poison. Just because something is natural does not make it safe; for example, tobacco and ethanol (alcohol) are both natural.”
Fructose gets directed towards fat formation or not, depends upon the energy status of your body.
High amount of fructose can be a problem, Fructose is not a problem!
“Knowing the metabolism of a small amount of fructose intake as a small portion of carbohydrate is not important.”
The majority of studies are based on isolated fructose consumption, which does not exist in people who prefer to consume whole foods (Fruits).
Fructose in Isolation is chronically harmful, whereas Acute Fructose in Isolation is not. A single high fructose meal will not cause liver dysfunction, but repeated meals can. The FDA does not control chronic toxins; it only regulates acute toxins.