Aerobic exercise training in the treatment of non‐alcoholic fatty liver disease related fibrosis

Linden, Melissa A.; Sheldon, Ryan D.; Meers, Grace M.; Ortinau, Laura; Morris, E. Matthew; Booth, Frank W.; Kanaley, Jill A.; Vieira‐Potter, Victoria J.; Sowers, James R.; Ibdah, Jamal A.; Thyfault, John P.; Laughlin, M. Harold; Rector, R. Scott

doi:10.1113/jp272235

Cited by 51 publications

(51 citation statements)

References 54 publications

(135 reference statements)

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“…; Linden et al . ). Inappropriate cholesterol metabolism has received considerable attention in human and animal studies of NAFLD, and has been observed to modulate multiple pathways triggering NASH development (Min et al .…”

Section: Introductionmentioning

confidence: 97%

“…High calorie, high fat diets (HFD) are associated with NAFLD risk and obesity in humans and are commonly utilized to induce hepatic steatosis in rodent models. However, chronic HFD-induced hepatic steatosis does not progress to non-alcoholic steatohepatitis (NASH) in rodent models (Matteoni et al 1999), whereas we and others have shown that the addition of refined sugar and/or cholesterol to an HFD induces NASH-like outcomes (Gan et al 2014;Bashiri et al 2016;Linden et al 2016). Inappropriate cholesterol metabolism has received considerable attention in human and animal studies of NAFLD, and has been observed to modulate multiple pathways triggering NASH development (Min et al 2012;Arguello et al 2015).…”

Section: Introductionmentioning

confidence: 98%

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Aerobic capacity mediates susceptibility for the transition from steatosis to steatohepatitis

Morris

McCoin

Allen

et al. 2017

The Journal of Physiology

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Low aerobic capacity increases risk for non-alcoholic fatty liver disease and liver-related disease mortality, but mechanisms mediating these effects remain unknown. We recently reported that rats bred for low aerobic capacity (low capacity runner; LCR) displayed susceptibility to high fat diet-induced steatosis in association with reduced hepatic mitochondrial fatty acid oxidation (FAO) and respiratory capacity compared to high aerobic capacity (high capacity runner; HCR) rats. Here we tested the impact of aerobic capacity on susceptibility for progressive liver disease following a 16-week 'western diet' (WD) high in fat (45% kcal), cholesterol (1% w/w) and sucrose (15% kcal). Unlike previously with a diet high in fat and sucrose alone, the inclusion of cholesterol in the WD induced hepatomegaly and steatosis in both HCR and LCR rats, while producing greater cholesterol ester accumulation in LCR compared to HCR rats. Importantly, WD-fed low-fitness LCR rats displayed greater inflammatory cell infiltration, serum alanine transaminase, expression of hepatic inflammatory markers (F4/80, MCP-1, TLR4, TLR2 and IL-1β) and effector caspase (caspase 3 and 7) activation compared to HCR rats. Further, LCR rats had greater WD-induced decreases in complete FAO and mitochondrial respiratory capacity. Intrinsic aerobic capacity had no impact on WD-induced hepatic steatosis; however, rats bred for low aerobic capacity developed greater hepatic inflammation, which was associated with reduced hepatic mitochondrial FAO and respiratory capacity and increased accumulation of cholesterol esters. These results confirm epidemiological reports that aerobic capacity impacts progression of liver disease and suggest that these effects are mediated through alterations in hepatic mitochondrial function.

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Section: Introductionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 98%

Aerobic capacity mediates susceptibility for the transition from steatosis to steatohepatitis

Morris

McCoin

Allen

et al. 2017

The Journal of Physiology

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“…Due to the high rates of individuals with hepatic fat accumulation, pharmaceutical, and nutritional strategies were developed to curb the damage of this disorder. Physical exercise has been extensively recommended for providing relevant actions in the battle against hepatic fat accumulation and metabolic disorders …”

Section: Introductionmentioning

confidence: 99%

“…Physical exercise has been extensively recommended for providing relevant actions in the battle against hepatic fat accumulation and metabolic disorders. [5][6][7][8][9] Different studies have elucidated the molecular pathways involved in the obesity-induced hepatic fat accumulation. Recently, Tabata et al 10 described the effects of the Cdc2-like kinase (CLK2) on the suppression of fatty acid oxidation and hepatic ketogenesis.…”

Section: Introductionmentioning

confidence: 99%

Exercise decreases CLK2 in the liver of obese mice and prevents hepatic fat accumulation

Muñoz

Gaspar

Kuga

et al. 2018

J of Cellular Biochemistry

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The accumulation of fatty acids in the liver associated with obesity condition is also known as nonalcoholic fatty liver disease (NAFLD). The impaired fat oxidation in obesity condition leads to increased hepatic fat accumulation and increased metabolic syndrome risk. On the other hand, physical exercise has been demonstrated as a potent strategy in the prevention of NAFLD. Also, these beneficial effects of exercise occur through different mechanisms. Recently, the Cdc2-like kinase (CLK2) protein was associated with the suppression of fatty acid oxidation and hepatic ketogenesis. Thus, obese animals demonstrated elevated levels of hepatic CLK2 and decreased fat acid oxidation. Here, we explored the effects of chronic physical exercise in the hepatic metabolism of obese mice. Swiss mice were distributed in Lean, Obese (fed with high-fat diet during 16 weeks) and Trained Obese group (fed with high-fat diet during 16 weeks and exercised (at 60% exhaustion velocity during 1 h/5 days/week) during 8 weeks. In our results, the obese animals showed insulin resistance, increased hepatic CLK2 content and increased hepatic fat accumulation compared to the Lean group. Otherwise, the chronic physical exercise improved insulin resistance state, prevented the increased CLK2 in the liver and attenuated hepatic fat accumulation. In summary, these data reveal a new protein involved in the prevention of hepatic fat accumulation after chronic physical exercise. More studies can evidence the negative role of CLK2 in the control of liver metabolism, contributing to the improvement of insulin resistance, obesity, and type 2 diabetes.

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“…These findings are consistent with the present study, where central adiposity was seen in concert with early liver injury and portal fibrosis in DDOST+/-mice fed a high AGE diet. Whether reiterates the complexity of the relationship between metabolic factors and liver injury, given that exercise is a feasible intervention to improve liver fibrosis in patients with NAFLD 217 and relates to adiposity in NAFLD 218 .…”

Section: Discussionmentioning

confidence: 99%

Novel role of AGE-R1/OST48 in the metabolome and proteome promoting ER stress in the kidney and liver

Zhuang¹

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The protein oligosaccharyltransferase-48 (OST48/AGE-R1) is integral to protein N-glycosylation in the endoplasmic reticulum (ER) but is also postulated to act as a membrane localised clearance receptor for advanced glycation end-products (AGE). AGE accumulation is implicated in liver injury, diabetic kidney disease and diabetes-associated metabolic disorders. To date, however, there has been minimal investigation into the role of OST48 in kidney and liver function under either physiological or diabetic conditions. Here we have used both global (DDOST+/-) and targeted (podocyte specific; DDOST+/-Pod-Cre ) knock-in mouse models to induce subtle increases in OST48.The burden of OST48 ligands, AGEs in these models, was modified by either dietary intervention or by the induction of diabetes to delineate the effects of increasing OST48 on the kidney and liver metabolome and proteome. Given previous studies, our postulate was that increasing OST48 would improve liver and kidney function in diabetes by facilitating removal of AGEs from the body.In the first study, we examined hepatic function and structure following global knock in of OST48 in combination with a therapeutic reduction in dietary AGE intake. Global knock-in of OST48 increased protein OST48 in the gastrointestinal tract, where it was highest in the duodenum. Both increasing gastrointestinal OST48 expression and/or greater consumption of AGEs modestly impaired liver function resulting in hepatic fibrosis. However, a combination of both high AGE dietary consumption and increased OST48 expression significantly exacerbated liver injury, but this was in the absence of steatosis. Interestingly, DDOST+/-mice had increased portal vein delivery and accumulation of hepatic AGEs which were associated with central adiposity, insulin secretory defects, shifting of fuel usage to fatty and keto-acids, and hepatic glycogen accumulation. These culminated in hepatomegaly along with hepatic ER and oxidative stress. This work is significant in that it revealed a novel role of the OST48 and AGE axis as a two-hit model of hepatic injury through ER stress, changes in fuel utilisation and impaired glucose tolerance.Our second and third studies aimed to delineate the physiological role of OST48 in the kidney through a global and podocyte-specific knock-in of OST48. Firstly, we investigated whether increased AGE excretion facilitated by modest increases in OST48, could prevent the development of diabetic kidney disease. This body of work is particularly significant, as to date there have been no studies examining whether elevating OST48 in diabetes is reno-protective, despite associative studies suggesting that a loss of OST48 is a pathological contributor to diabetes complications.

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Aerobic exercise training in the treatment of non‐alcoholic fatty liver disease related fibrosis

Cited by 51 publications

References 54 publications

Aerobic capacity mediates susceptibility for the transition from steatosis to steatohepatitis

Aerobic capacity mediates susceptibility for the transition from steatosis to steatohepatitis

Exercise decreases CLK2 in the liver of obese mice and prevents hepatic fat accumulation

Novel role of AGE-R1/OST48 in the metabolome and proteome promoting ER stress in the kidney and liver

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