The journal articles show two contributory pathways to non-alcoholic fatty liver disease (NFALD) and thus to insulin resistance (IR) and their comorbidities, that of a high carb diet with high sugar, and that of a diet high in trans-fats, and or polyunsaturated fats which are subject in vivo to oxidation.  Another part of the library of journal articles on rancid (oxidized) polyunsaturated fats is at http://healthfully.org/dja/id4.html  and http://healthfully.org/dja/id5.html , and http://healthfully.org/dja/id2.html   -jk.   

“A recent meta-analysis presented at the Annual Meeting of the American Association for the Study of Liver Diseases(AASLD) reported that weight-loss surgery leads to improvement and or resolution of NASH [extreme form of NAFLD] in around 80% of patients.^[26] Wiki.  This is strong evidence that diet can resolve NASH, NAFLD, and IR.  Other studies of bariatric surgery show a rapid resolution of type-2 diabetes—before significant weight loss—which shows that fasting and thus diet can cure T2D, at http://healthfully.org/dja/id6.html —jk.

This study chose overweight volunteers because they were more likely to have genes that promote fat storage in the liver than those who were lean.  A second question is as to feeding with sugar (one that hadn’t been address at that time) was if the sugar promoted the storage of existing fat or de novo fat production (DNL).  A gene has been found which prevents the synthesized fat from being hydrolyzed into free fatty acids for transport in the blood, thus this gene variant promotes storage of DNL. These volunteers were chosen.  Such common variation in a population is not surprising given the variations in diet world-wide, and thus differential selective forces based upon diet.  Populations in northern regions would only have a short access to fruits, thus little selective advantage to having a gene for a problem that doesn’t exist.  In general it has been found that even modest percentage of weight loss results a far more proportional loss in liver fat (and assumable pancreatic fat).  Since the accumulation of fat in the liver has negative selection, there is positive selection for the fix.     From the full article:  “Previous weight-loss studies addressing the effects of weight loss on liver fat have shown that even small decreases in body weight result in considerable decreases in liver fat. Loss of 3% (44), 9% (45), 7% (46), 10% (47), 10% (47), and 14% (47) of body weight has decreased liver fat content as measured by using ¹H-MRS by 31% (44), 46% (45), 41% (46), 37% (47), 29% (47), and 40% (47), respectively.“  This evidence explains why with the short fast following bariatric surgery around 90% are cured of T2D, and why diet has such a rapid effect upon medication for T2D.  The bottom study is of another contributing factor to NAFLD, abnormal oils; tested were trans and oxidized polyunsaturated fats.  ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^

http://ajcn.nutrition.org/content/96/4/727.short

September 5, 2012, doi:10.3945/​ajcn.112.038695, Am J Clin Nutr October 2012,  vol. 96 no. 4 727-734

Effect of short-term carbohydrate overfeeding and long-term weight loss on liver fat in overweight humans^1,2,3

Background: Cross-sectional studies have identified a high intake of simple sugars as an important dietary factor predicting nonalcoholic fatty liver disease (NAFLD).

Objective: We examined whether overfeeding overweight subjects with simple sugars increases liver fat and de novo lipogenesis (DNL) and whether this is reversible by weight loss.

Design: Sixteen subjects [BMI (kg/m²): 30.6 ± 1.2] were placed on a hypercaloric diet (>1000 kcal simple carbohydrates/d) for 3 wk and, thereafter, on a hypocaloric diet for 6 mo. The subjects were genotyped for rs739409 in the PNPLA3 gene.  Before and after overfeeding and after hypocaloric diet, metabolic variables and liver fat (measured by proton magnetic resonance spectroscopy) were measured. The ratio of palmitate (16:0) to linoleate (18:2n−6) in serum and VLDL triglycerides was used as an index of DNL.

Results: Carbohydrate overfeeding increased weight (±SEM) by 2% (1.8 ± 0.3 kg;P < 0.0001) and liver fat by 27% from 9.2 ± 1.9% to 11.7 ± 1.9% (P = 0.005). DNL increased in proportion to the increase in liver fat and serum triglycerides in subjects with PNPLA3-148II but not PNPLA3-148MM. During the hypocaloric diet, the subjects lost 4% of their weight (3.2 ± 0.6 kg; P < 0.0001) and 25% of their liver fat content (from 11.7 ± 1.9% to 8.8 ± 1.8%; P < 0.05).

Conclusions: Carbohydrate overfeeding for 3 wk induced a >10-fold greater relative change in liver fat (27%) than in body weight (2%). The increase in liver fat was proportional to that in DNL. Weight loss restores liver fat to normal. These data indicate that the human fatty liver avidly accumulates fat during carbohydrate overfeeding and support a role for DNL in the pathogenesis of NAFLD. This trial was registered at www.hus.fi as 235780.

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The first question is “Why does the body tightly regulate blood glucose and so too does cells?”  The main reason is that simple glucose and even more so fructose, they are reactive chemical that cause through glycation damage to cells.  As a way to limit the damage, the cells burn them in the mitochondria or convert them to stable fats.   “the two sugars have very different metabolic fates in human metabolism. Unlike glucose, which is metabolized widely in the body, fructose is metabolized almost completely in the liver in humans, where it is directed toward replenishment of liver glycogen and triglyceride synthesis.  Under one percent of ingested fructose is directly converted to plasma triglyceride.^[2] 29% - 54% [what of FFF, suspect tobacco science] of fructose is converted in liver to glucose, and about quarter of fructose is converted to lactate. 15% - 18% is converted to glycogen.^[3] Glucose and lactate are then used normally as energy to fuel cells all over the body.”  .  subjects with the 148II variant of the gene for a lipase, PNPLA3, subjects with the 148MM variant that is associated with fatty liver but low plasma triglycerides… An important mechanism is de novo lipogenesis (DNL), the synthesis of the SFA palmitate, from glucose, fructose, or both… The results show for the first time a link between excess dietary sugar and the accumulation of liver fat by DNL, a pathway uniquely stimulated by dietary sugar

http://ajcn.nutrition.org/content/96/4/685.full

Why do sweets fatten our livers?^1,2,3

1.      Lisa C Hudgins

+Author Affiliations

+Author Notes

• ↵2 Supported in part by The Starr Foundation.

1.      ↵³Address correspondence to LC Hudgins, The Rogosin Institute, 310 East 67th Street, Room 2-43A, New York, NY 10021. E-mail: lih2013@nyp.org.

See corresponding article on page 727.

In recent years, the search for lifestyle changes that will slow the obesity epidemic and its adverse sequelae has turned to dietary sugar. A substantial number of calories come from beverages and desserts made with sucrose or high-fructose corn syrup, which are absorbed as a mixture of glucose and fructose. But apart from weight gain from excess sweet calories, what are the specific metabolic consequences that are harmful to health?

The best-documented adverse effect known for decades is the dyslipidemia that develops with the ingestion of large amounts of sugar, even when substituted calorie for calorie for fat (1). An important mechanism is de novo lipogenesis (DNL), the synthesis of the SFA palmitate, from glucose, fructose, or both. There is a marked increase in DNL after excess carbohydrate calories (2) or the iso-caloric substitution of dietary glucose or mixed sugars for starch, complex carbohydrate, or fat (1, 3). Although the absolute quantity of synthesized fat is small, there are large increases in plasma triglyceride concentrations and the ratio of palmitate to the essential fatty acid linoleate (lipogenic index). Triglyceride synthesis and secretion by the liver is increased by the generation of palmitate, glycerol (the backbone of triglyceride), and malonyl coenzyme A (an intermediate that inhibits fatty acid oxidation and channels fatty acids into triglyceride). The fructose component of dietary sugar is particularly lipogenic because of its uniquely high first-pass clearance by the liver. Increased plasma VLDL triglyceride, via cholesterol ester exchange protein, produces the full spectrum of lipid abnormalities (high triglycerides, small dense LDL, and low HDL) that accelerate atherosclerosis. Conversely, DNL and triglyceride synthesis are rapidly suppressed during weight loss (2).

The current study by Sevastianova et al (4) in this issue of the Journal expands the lipogenic effects of dietary sugar beyond dyslipidemia to include fatty liver. The results show for the first time a link between excess dietary sugar and the accumulation of liver fat by DNL, a pathway uniquely stimulated by dietary sugar. A small number of nondiabetic, overweight adults, half of whom had fatty livers, consumed an excess of sugar as candy and beverages for 3 wk. Details of the overall macronutrient composition of the diets were not provided, but the excess sugar intake was close to the 80th percentile of intake in the United States (5). Dietary compliance was judged to be acceptable because the amount of weight gain was that expected for the excess of calories. The results showed that a 2% increase in body weight and similar increases in subcutaneous and visceral adipose tissue were accompanied by a 27% increase in liver fat measured by proton magnetic resonance spectroscopy. Large increases were also observed in fasting plasma VLDL and total triglycerides and DNL, as reflected by the lipogenic index in triglycerides. HDL cholesterol also decreased (LDL size was not measured). These changes were reversed at the end of a 6-mo hypocaloric, low-sugar dietary period. Importantly, for the entire group, the increase in the lipogenic index was positively correlated with the increase in liver and serum triglycerides.

Hepatic steatosis affects a large fraction of US obese adults and children and may progress to nonalcoholic steatohepatitis, cirrhosis, and liver failure. The implication that a persistent excess of calories as dietary sugar can cause or exacerbate fatty liver by DNL, a pathway unique to dietary sugars, lends additional support to public health recommendations to limit dietary sugars. The increased liver fat resulting from increased DNL and the imbalance between triglyceride synthesis and secretion may increase oxidative stress, inflammation, and insulin resistance (6). Indeed, in this study, liver enzymes significantly increased after the high-carbohydrate period, and there was a trend for an increase in fasting serum insulin. Whether triglycerides enriched in SFAs are more damaging to human liver (7) is unknown but deserves further study.

The most tantalizing finding is also the most tentative given the small number of subjects. Unlike subjects with the 148II variant of the gene for a lipase, PNPLA3, subjects with the 148MM variant that is associated with fatty liver but low plasma triglycerides did not show an increase in liver fat and plasma triglyceride in proportion to DNL. The authors proposed that this was because of impaired lipolysis of intrahepatic triglycerides and reduced VLDL assembly and secretion. However, given that the increases in liver and plasma triglycerides were similar between groups, this genotype does not appear to affect lipogenic sensitivity to dietary carbohydrate, and other metabolic differences, including response to high-fat diets, must be explored. Alternatively, the relation between the lipogenic index and DNL may have been distorted if the lipase is selective for specific fatty acids.     The small number of subjects sampled precludes testing for other potential confounding variables.

In conclusion, the results provide the impetus for the measurement of liver and plasma triglycerides and DNL after a carbohydrate challenge in a larger number of ethnically diverse subjects tested for genes associated with fatty liver. In this way, the genetic heterogeneity for the lipogenic effects of dietary sugar will be defined. Dietary recommendations to restrict sugars can then have a stronger scientific rationale and target those at greatest risk and the specific mechanism or mechanisms responsible.

http://ajcn.nutrition.org/content/96/4/727.short

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A second issue as to the development of fatty liver is that of abnormal fats, namely trans and oxidized polyunsaturated fats.  This is one more way through the contributing to the disruption of the metabolic regulatory system that they are a cause for CVD and MI.  The experiment below likely applies to humans--jk. 

http://www.biomedcentral.com/content/pdf/1743-7075-8-65.pdf Full published by BioMed Central (Open Access Publishers) at http://nutritionandmetabolism.biomedcentral.com/articles/10.1186/1743-7075-8-65 2/11

The intake of high fat diet with different trans fatty acid levels differentially induces oxidative stress and non alcoholic fatty liver disease (NAFLD) in rats

Abstract

Background: Trans-fatty acids (TFA) are known as a risk factor for coronary artery diseases, insulin resistance and obesity accompanied by systemic inflammation, the features of metabolic syndrome. Little is known about the effects on the liver induced by lipids and also few studies are focused on the effect of foods rich in TFAs on hepatic functions and oxidative stress. This study investigates whether high-fat diets with different TFA levels induce oxidative stress and liver dysfunction in rats.

Methods:  Male Wistar rats were divided randomly into four groups (n = 12/group): C receiving standard-chow; Experimental groups that were fed high-fat diet included 20% fresh soybean oil diet (FSO) The intake of high fat diet with different trans fatty acid levels differentially induces oxidative stress and non-alcoholic fatty liver disease (NAFLD) in rats.

Results:  A liver damage was observed in rats fed with high-fat diet via increase of liver lipid peroxidation and decreased hepatic antioxidant enzyme activities (superoxide dismutase, catalase and glutathione peroxidase). The intake of oxidized oil led to higher levels of lipid peroxidation and a lower concentration of plasma antioxidants in comparison to rats fed with FSO. The higher inflammatory response in the liver was induced by MG diet. Liver histopathology from OSO and MG groups showed respectively moderate to severe cytoplasm vacuolation, hypatocyte hypertrophy, hepatocyte ballooning, and necroinflammation.

Conclusion: It seems that a strong relationship exists between the consumption of TFA in the oxidized oils and lipid peroxidation and non alcoholic fatty liver disease (NAFLD). The extent of the peroxidative events in liver was also different depending on the fat source suggesting that feeding margarine with higher TFA levels may represent a direct source of oxidative stress for the organism. The present study provides evidence for a direct effect of TFA on NAFLD.

From body of article, selected by JK:

List of Abbreviations

SFA: saturated fatty acid

MUFA: monounsaturated fatty acid

PUFA: polyunsaturated fatty acid

TFAs: trans fatty acids

HDL: high density lipoprotein

LDL: low density lipoprotein

ALP: alkaline phosphatase

AST: aspartate transaminase

ALT: alanine transaminase

LDH: lactate dehydrogenase

SOD: superoxide dismutase

GPx: glutathione peroxidase

GR: glutathione reductase

 CAT: catalase

 CD: conjugated dienes

 MDA:  malondialdehyde

CVD: cardiovascular disease

 NAFLD: non alcoholic fatty liver disease

Others not listed

fresh soybean oil (FSO) diet

oxidized soybean oil (OSO) diet

margarine (MG) diet

control (C) diet (standard rat chow)

Animal treatment

Male adult Wistar rats (Central Pharmacy, Tunisia), weighing about 200 to 280 g, were housed at 22 ± 3°C, with 12- hour light-dark periods, a 40% minimum relative humidity and free access to water and standard diet: protein 17% (methionine and choline accounting 3000 and 2720 milligrams per kilogram, respectively), carbohydrate 62%, lipids 4%, ash 7%, and moisture 10% (SICO, Sfax, Tunisia). All the breeding phases and experiments were conformable to the rules of the Tunisian Society for the Care and Use of Laboratory Animals. All experiments were conducted at the animal facilities of the faculty of Medicine, Monastir; with the approval of the Faculty of Medicine Ethics committee. After acclimatization to the laboratory conditions for one week, the animals were divided into 4 groups of 12 animals each. Group C included the control animals and received standard chow. Experimental groups that were fed high-fat diet included 20% fresh soybean oil diet (FSO), 20% oxidized soybean oil diet (OSO) and 20% margarine diet (MG). Each group was kept on the treatment for 4 weeks. Water and food consumption and the individual animal body-weight were recorded daily throughout the experiment. At the end of the experimental period, the rats were kept fasting overnight and were sacrificed under diethyl ether anesthesia.

Biochemical indicators of liver function

The levels of plasma hepato-specific enzymes such as, ALP and LDH were significantly increased (p < 0.05) in high-fat fed rats compared to control (Table 3). Feeding (OSO) led to significant higher levels of AST, ALP and LDH in comparison to fresh oil fed group (p < 0.05). Enhanced levels of plasma ALT and AST are indicative of liver damage [43]. Plasma ALP is a sensitive detector for intrahepatic and extrahepatic bile obstruction [44]. It is well known that dietary fat sources strongly influence several biochemical variables both in plasma and in biological membranes [45, 46, 47].  Consumption of OSO and MG diets causes a significant increase of biochemical indicators of liver damage. We noticed a close positive correlation between TFA levels in dietary fat and AST, ALAT, ALP and LDH (Table 4). These results revealed hepatic damage in rats consumed TFA.

Liver's Lipid peroxidation

 … This phenomenon plausibly alters cell membrane structure, including redefining lipid raft and non-raft regions in size, organization and composition. Lipid rafts are important for cellular signalling, as they provide docking sites for receptors, co-receptors and mediators including adhesion molecules [55]. Recent animal experiments indicate that TFAs impair fat cell membrane fluidity. When TFAs are incorporated into cell membranes, the membrane fluidity is reduced and the cells do not function as well. The resulting effect is then to promote further production of reactive oxygen species which explain the increase in lipid peroxidation in groups fed with TFAs diet.

Histopathological lesions

… Feeding OSO for four weeks, rat's liver showed increased incidences of hepatocytes hypertrophy (Figure4c, black triangle), fat deposition (Figure 4c, thin arrow) and infiltration of a mixed population of inflammatory cells in the liver, as well as ballooning degeneration of hepatocytes characterized by cell swelling with empty intracellular content, indicating cell necrosis (Figure 4d, thick arrow). 

Declarations

Acknowledgements

This research was supported by a grant from the 'Ministère de l'Enseignement Supérieur et de la Recherche Scientifique" UR03ES08 "Nutrition Humaine et Désordres Métaboliques" University of Monastir and 'DRT-USCR-Spectrométrie de masse. We are grateful to the anonymous reviewers for their valuable comments and remarks. We thank Mr. Arafet Dhibi for the critical review English Grammar of the manuscript.