Beyond its use for protein folding utility …

Trehalose Blocks Fatty Liver Disease
In diets that are high in sugars

By Will Block

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the world.1 Closely linked to obesity, more than 1 billion individuals worldwide have this highly morbid disease. NAFLD is characterized in its earliest stages by excessive hepatic fat deposition and in later stages by steatohepatitis, fibrosis, cirrhosis, liver failure, and progression to hepatocellular carcinoma. Lamentably, few treatments exist that are efficacious, although weight loss can reduce the buildup of fat in the liver.

Until now! Important new research indicates that the disaccharide trehalose, a natural sugar, may be able to prevent NAFLD.2 Although vertebrates (including humans) cannot synthesize trehalose, exogenous administration of trehalose to mammalian cells is thought to be beneficial for protein misfolding disorders, also called called conformational disorders (see sidebar below, “Other Uses of Trehalose”).

Reducing Misfolding Effects

Life Enhancement has published several articles that focus on reducing the conformational disorders though the use of trehalose and other osmolytes. An important class of natural chemical chaperones that help stabilize the proper folding conformation of proteins are the osmolytes (see “The Origami of Aging” in the September 2008 issue, “Beta-Alanine Fights Alzheimer’s Amyloid” in the September 2009 issue, “Maintain Your Youthful Edge" in the April 2010 issue, “Trehalose for Dry Eyes” in the August 2011 issue, “Housekeeping for a Longer Life: Clearing Unwanted or Toxic Cellular Debris by Inducing Autophagy With the Sugar Trehalose”in the September 2012 issue of Life Extension News, “Life Extension Methuselahs” in the February 2014 issue, and “Trehalose, An Inducer of Autophagy, May Be a Possible Protectant Against Amyloid Aggregation” in the November 2015 issue of Life Extension News.)


Closely linked to obesity, more than 1
billion individuals worldwide have
this highly morbid disease.


Liver Transport Prevented and Cleaned Up After

In the new research,2 conducted by Brian DeBosch, MD, PhD and colleagues at Washington University School of Medicine, St. Louis, Missouri, trehalose is shown to treat NAFLD by inhibiting certain sugar transporters that allow the passage of fructose into the liver. Fructose is thus kept out of the liver preventing fat buildup, while also triggering a cellular housekeeping process known as autophagy that cleans up excess fat buildup inside liver cells.

Fructose and Fatty Liver


Important new research indicates that
the disaccharide trehalose, a natural
sugar, may be able to prevent NAFLD.


“In general, if you feed a mouse a high-sugar diet, it gets a fatty liver,” said first author DeBosch.3 “We found that if you feed a mouse a diet high in fructose plus provide drinking water that contains three percent trehalose, you completely block the development of a fatty liver. Those mice also had lower body weights at the end of the study and lower levels of circulating cholesterol, fatty acids and triglycerides.”

Triglyceride Accumulation


Protein before and after folding
According to DeBosch, there is evidence that NAFLD develops as the liver works hard to process dietary sugar, especially fructose, found naturally in fruit but also added as high-fructose corn syrup to soft drinks and many processed foods. Ultimately, the body stores fructose in the liver as fats called triglycerides. In severe cases of the disease, the fat can build up to toxic levels that may eventually require a liver transplant.

Trehalose is a natural sugar found in plants and insects and consists of two glucose molecules bound together. It is approved by the FDA for human consumption, yet DeBosch cautions that more research is required before trehalose could be tested in people with NAFLD as part of a clinical trial. Clinical trials with humans are the “gold standard.” Such research, however, given the length of time such studies require, would make them impractical in humans.

Other Uses of Trehalose

From Durk Pearson & Sandy Shaw (see “Natural Sugar and Osmolyte Trehalose May Be a Novel Treatment for Parkinson’s—And Is Safe and Inexpensive” in the January 2014 issue of Life Extension News):

“Trehalose is a natural sugar1 that acts as an osmolyte by preventing abnormal protein folding in the endoplasmic reticulum of cells, the special organelle where proteins are synthesized and folded. Trehalose guides proteins into their proper shape by preventing water from interacting with the protein surface in the process of folding,2 which would interfere with the complex interactions of the hydrophobic (water avoiding) and hydrophilic (water attracted) parts of the protein from interacting properly (imagine a protein molecule as a complex origami sculpture with lots of moving parts). We take trehalose as a daily supplement in a mixture of several osmolytes for helping proteins fold properly, as the aggregation of improperly folded proteins occurs as part of the aging process. Several serious diseases, such as Parkinson’s and Alzheimer’s disease, are associated with improperly folded, aggregated proteins. In the case of Parkinson’s, the aggregated protein is alpha-synuclein.


Trehalose guides proteins into their
proper shape by preventing water
from interacting with the protein
surface in the process of folding.


“Trehalose has been reported in recent publications to inhibit protein aggregation that occurs in Alzheimer’s disease, Huntington’s disease3 and prion disease. The second page of a recent paper4 shows the molecular structure of trehalose, with its large numbers of hydroxyl groups hanging off the trehalose ring structure. These hydroxyl groups are able to bind and control the movement of parts of complex molecules with large numbers of hydrogen bonds (as found in proteins). Thus, trehalose is made to order as a tool for controlling the folding of proteins.


We take trehalose as a daily
supplement in a mixture of several
osmolytes for helping proteins fold
properly, as the aggregation of
improperly folded proteins occurs
as part of the aging process.


“The researchers tested trehalose on the formation of mature A53T AS (alpha synuclein) protofibrils (a form of AS folding that may be neurotoxic for dopaminergic neurons, the type of neurons that are dysfunctional in Parkinson’s disease). The data showed that “trehalose at high concentration could slow down the formation of beta-sheet aggregates during the early period of incubation, stabilize and increase the partially-folded oligomers or beta-sheet-rich protofilaments which increase the ThT fluorescence intensity [the instrumental measure of beta-sheet aggregates], and prevent the formation of the mature A53T AS fibrils during the late period of incubation.”4

“As the authors explain, there are three hypotheses for how trehalose stabilizes protein folding: water-layer with preferential exclusion, water-replacement, and mechanical-entrapment. The authors discuss how these hypotheses may explain, at least in part, the results they observed.


“Trehalose has been reported in
recent publications to inhibit
protein aggregation that occurs in
Alzheimer’s disease, Huntington’s
disease and prion disease.”


“The researchers suggest that a better understanding of the neurotoxicity of the various species of aggregated AS will be ‘crucial’ for understanding how to use trehalose for best results. In the meantime, they report that trehalose has been reported in other research to enhance autophagy (a process akin to self-eating, whereby unneeded or toxic cellular debris is disposed of)5 and to have anti-inflammatory effects; both of these effects are beneficial in Parkinson’s disease.4 Trehalose has also been shown to increase lifespan in the nematode Caenorhabditis elegans.4

1. For example, mushrooms contain up to 10–25% trehalose by dry weight. See Higashiyama. Novel functions and applications of trehalose. Pure Appl Chem. 74(7):1263-69 (2002).

2. Street et al. A molecular mechanism for osmolyte-induced protein stability. Proc Natl Acad Sci USA. 103(38):13997-14002 (2006).

3. Tanaka et al. Trehalose alleviates polyglutamine-mediated pathology in a mouse model of Huntington disease. Nat Med. 10(2):148-54 (2004).

4. Yu et al. Trehalose inhibits fibrillation of A53T mutant alpha-synuclein and disaggregates existing fibrils. Arch Biochem Biophys. 523:144-50 (2012).

5. Sarkar et al. Trehalose, a novel mTOR-independent autophagy enhancer, accelerates the clearance of mutant Huntingtin and alpha synuclein. J Biol Chem. 282(8):5641-52 (2007).

Are His Patients Children?

“I can’t recommend it to my patients yet,” said DeBosch, who sees patients at St. Louis Children’s Hospital.3 “We know the mice that received drinking water with three percent trehalose lost weight, and we suspect that weight loss was due to loss of fat, but we can’t be certain that’s the only effect. We need more studies to make sure they were not losing bone or muscle mass.”

Many of us know that reducing the ingestion of foods with sugar and especially high fructose corn syrup is a good idea, and now we have one more good reason to understand why this is so.


If you feed a mouse a diet high in
fructose plus provide drinking water
that contains three percent trehalose,
you completely block the
development of a fatty liver.


Fighting Sugar with Sugar

The role of dietary sugar has been implicated in conditions such as obesity, insulin resistance and high blood pressure, among other markers of metabolic syndrome. And we can include NAFLD. So it might seem unreasonable to treat a condition that is caused at least in part by sugar consumption, with more sugar. But the effect of trehalose on fructose transport into the liver gives some clues to how it works.

In prior research,4 DeBosch and his colleagues—including senior author Kelle H. Moley, MD, the James P. Crane Professor of Obstetrics and Gynecology—showed that a protein on the surface of liver cells called GLUT8 is required for mice to develop fatty livers in response to a high-fructose diet. But if GLUT8 is blocked, the development of hepatic steatosis can be prevented.

Looked for GLUT8 Blockers

“We knew that GLUT8 carries large amounts of fructose into liver cells,” DeBosch said. “So we looked for things that block GLUT8. We were interested in investigating trehalose because it has been studied in models of neurodegenerative disorders such as prion disease or amyotrophic lateral sclerosis—Lou Gehrig’s disease. In mice, trehalose appears to cause brain cells to swallow up abnormal proteins that accumulate in these conditions. We wondered if it would do the same for fat buildup in liver cells.”3


NAFLD develops as the liver
works hard to process dietary sugar,
especially fructose, found naturally in
fruit but also added as high-fructose
corn syrup to soft drinks and
many processed foods.


Succinctly, the researchers found that trehalose blocks the transport of sugar energy into liver cells, effectively causing the cells to behave as if they’re starving and thereby turning on the process of autophagy, whereby the fat already stored in the cell is consumed. However, this process is a double-edged sword and along with fat, might drain cells of proteins, which may not be desirable. There is no proof of this.

Autophagy Triggering

“We appear to be hijacking the liver’s own starvation pathway using a sugar already found in nature,” DeBosch said.3 “We think autophagy may be triggered when the cell is stressed with too much fat or protein buildup. The cell turns on autophagy in response to the stress or because of a lack of energy and starts gobbling stuff up. It’s a house cleaning.”

DeBosch expects that other researchers may turn their attention to trehalose in order to understand exactly how this sugar hijacks cell signaling pathways. DeBosch also thinks that the potential for this treatment strategy goes further than neurodegenerative and metabolic diseases.

Trehalose as Preventative


Brian DeBosch, MD, PhD, and his colleagues showed that a natural sugar called trehalose prevents fatty liver disease in mice. (Photo: Robert Boston/School of Medicine)
Trehalose prevents a diet high in fructose, or fruit sugar, from causing fatty liver disease. Fructose is thought to be a major contributor to the disease, and high-fructose corn syrup is used in soft drinks and many processed foods.

Trehalose has also gained attention for its ability to induce cellular autophagy and mitigate diseases related to pathological protein aggregation. Despite decades of ubiquitous use as a nutraceutical, preservative, and humectant, its mechanism of action remains elusive.

In the current DeBosch paper, the researchers showed that trehalose inhibited members of the GLUT family of glucose transporters. Trehalose-mediated inhibition of glucose transport induced AMPK (adenosine 5′-monophosphate–activated protein kinase)–dependent autophagy and regression of hepatic steatosis in vivo and a reduction in the accumulation of lipid droplets in primary murine hepatocyte cultures. The data indicate that trehalose triggers beneficial cellular autophagy by inhibiting glucose transport. In summary, we have a conclusion with a gigantic application that may alleviate suffering on a grand scale.

References

  1. Loomba R, Sanyal AJ. The global NAFLD epidemic. Nat Rev Gastroenterol Hepatol. 2013 Nov;10(11):686-90.
  2. DeBosch BJ, Heitmeier MR, Mayer AL, Higgins CB, Crowley JR, Kraft TE, Chi M, Newberry EP, Chen Z, Finck BN, Davidson NO, Yarasheski KE, Hruz PW, Moley KH. Trehalose inhibits solute carrier 2A (SLC2A) proteins to induce autophagy and prevent hepatic steatosis. Sci Signal. 2016 Feb 23;9(416):ra21. doi:10.1126/scisignal.aac5472. PubMed PMID: 26905426.
  3. Strait JE. Natural sugar may treat fatty liver disease. The Source https://source.wustl.edu/2016/02/natural-sugar-may-treat-fatty-liver-disease/. February 23, 2016. Accessed February 27, 2016.
  4. Debosch BJ, Chen Z, Saben JL, Finck BN, Moley KH. Glucose transporter 8 (GLUT8) mediates fructose-induced de novo lipogenesis and macrosteatosis. J Biol Chem. 2014 Apr 18;289(16):10989-98.


Will Block is the publisher and editorial director of Life Enhancement magazine.

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