Low-carbohydrate ketogenic diets, glucose homeostasis, and nonalcoholic fatty liver disease


#1

I have been wondering about the Keto Diet and non alcoholic fatty liver disease (NAFLD.) I decided to do a little reading and found this article. It leaves me feeling a bit uneasy about KD and NAFLD. I know the authors say that the relationship between rodent and human is not quite clear.

I am hoping that there are more recent studies done that indicate that humans do not react the same as rodents.

ABSTRACT:

RECENT FINDINGS:

Low-carbohydrate diets have been shown to promote weight loss, decrease intrahepatic triglyceride content, and improve metabolic parameters of patients with obesity. These ketogenic diets also provoke weight loss in rodents. However, long-term maintenance on a ketogenic diet stimulates the development of NAFLD and systemic glucose intolerance in mice. The relationship between ketogenic diets and systemic insulin resistance in both humans and rodents remains to be elucidated.

SUMMARY:

Because low-carbohydrate ketogenic diets are increasingly employed for treatment of obesity, NAFLD, and neurological diseases such as epilepsy, understanding the long-term systemic effects of low-carbohydrate diets is crucial to the development of efficacious and safe dietary interventions.

ARTICLE:


skipped down to:

Ketogenic diets and NAFLD in humans and rodents


Ketogenic diets have been extensively studied in rodents. Using a micronutrient supplemented KD (Bio-Serv F3666) very high in fat (93.3%kcal), very low in carbohydrate (1.8%), and also reduced in protein (4.7%), Meratos-Flier and colleagues observed that mice lose weight, develop ketosis, and induce hepatic gene expression signatures that suggest reduced DNL and increased FAO [[40*]]. To explore the relationships among KD, IHTG, and NAFLD, Garbow et al. maintained C57BL/6J mice for 12 weeks on either (i) Bio-Serv F3666 KD; (ii) a high-fat (40%kcal) ‘Western’ diet (WD) also enriched in sucrose (40%); or (iii) a standard low-fat (13%kcal) polysaccharide-rich chow control diet [[41**]]. The KD is reduced in protein content due to the fact that induction of ketosis in rodents requires restriction of not only carbohydrates but also protein [[42]]. Mice fed the KD for 12 weeks were lean, euglycemic, ketotic, and hypoinsulinemic, but were glucose intolerant, and exhibited NAFLD. MRS revealed that KD-fed mice accumulate hepatic lipid within 3 weeks after initiation of the diet, and the hepatic gene expression signature for DNL (encoded mediators of SREBP-1c, FAS, ACC1, SCD1) was suppressed compared to livers of chow-fed controls. In contrast, mice fed the WD ultimately accumulate higher IHTG than KD-fed animals, but do so much more slowly, and as expected due to the high sucrose content, induce mediators of DNL. Intriguingly, unlike steatotic livers of WD-fed mice, livers of KD-fed mice developed hepatic endoplasmic reticulum (ER)-stress, inflammation, macrophage accumulation, and hepatocellular injury, and only KD-fed mice exhibited elevated serum ALT concentrations. A number of non-mutually exclusive mechanisms may account for the murine hepatic phenotypes observed with this KD. First is the prospective influence of choline and methionine deficiencies. While choline-replete rodent diets are supplemented to contain ~2.5 g/kg, BioServ F3666 KD is not supplemented, and therefore contains only 200–300 mg/kg naturally-derived from the fat sources. Methionine content in this KD, derived from casein, is also reduced, at 2.2 g/kg, whereas methionine-replete diets contain ~4 g/kg. A second prospective contributor to the NAFLD signatures in KD-fed mice is overall reduction of protein: classical studies indicate that diets containing <14% protein retard normal growth, reproduction, and lactation in mice [[43]. A third prospective influence is cellular injury though ER stress-inducing membrane remodeling in periportal hepatocytes that receive more fat than can be oxidized or exported via VLDL secretion. Fourth, ceramide production within macrophages or hepatocytes, favored by high intracellular concentrations of saturated fatty acids, may also trigger the inflammasome, whose biomarkers were selectively elevated in livers of KD-fed mice. Finally, splice variants of the insulin-sensitizing nuclear receptor transcription factor PPARγ may exhibit distinct activities in different steatotic contexts. While the ‘adipocyte’ isoform form, PPARγ2, was induced in livers by WD, the `macrophage’ isoform PPARγ1 was selectively induced in livers of KD-fed mice.

Hepatic fibroblast growth factor 21 (FGF21) has emerged as a key regulator of hepatic metabolism, glucose, and fatty acid oxidative flux, and insulin sensitivity [[44], [45]. KD feeding of Fgf21 −/− mice leads to weight gain, reduced ketosis, and hepatic steatosis relative to KD-fed wild type controls in two weeks, consistent with impaired ability of the liver to oxidize fatty acids in the absence of FGF21 [[46]. Indeed, serum FGF21 concentrations are elevated in patients with diagnosed NAFLD, and obesity is an FGF21-resistant state [[47], [48]. Fgf21 mRNA is markedly induced in livers of mice fed either KD or WD for 12 weeks [[41**].


(bulkbiker) #2

Is that the one where the “ketogenic” diet fed to the mice was composed almost entirely of vegetable fat? Crisco?
Do you intend to eat Crisco on your diet … if so you may turn into that mouse…
Most people (all?) who follow a keto way of eating report that NAFLD clears up with weight loss.
Thankfully we aren’t mice and we don’t have mouse metabolisms so any conclusions drawn from mice studies are not really relevant to people.


(Frank) #3

Being in maintenance myself, this has certainly crossed my mind. There was a poster a while back who described keto as a furnace and a bridge. A furnace to burn down our old eating habits and heal our metabolism. A bridge to a healthy way of eating. Once healed, or as healed as I can get, I plan on introducing new foods into my diet slowly to see how I can handle them. It may come down to I can neither handle them mentally and/or metabolically, but at least the experiment was done and I can move on. For example, as a home brewer, I have cut waaaayyyyy back on my brewing and therefore beer intake over the past 8 months. I don’t want to let go of that hobby but my reaction to even 3-4 beers in a sitting lately has been pretty unpleasant. Is this glucose intolerance? Who knows.


#4

Here is what Bio-Serve reports is in Product# F3666 - Ketogenic Diet:
Lard, Butter, Corn Oil, Casein, Cellulose, Mineral Mix, Vitamin Mix, Dextrose.

They go on to say: “These are typical amounts of nutrients calculated from
available information. Actual assay results may vary.
For more information contact Jaime , Ph.D.
Phone: 800-996-
ext. *** (U.S. and Canada)
908-284-
** (International)
Email: ******@bio-serv.com.”

The Nutritional Profile for the Bio-Serve provided by them is found at:

-I- don’t see enough information there to draw a conclusion about the amount of corn oil used.


(bulkbiker) #5

Must have been a different study … however does your well formulated ketogenic diet look like this?

“Using a micronutrient supplemented KD (Bio-Serv F3666) very high in fat (93.3%kcal), very low in carbohydrate (1.8%), and also reduced in protein (4.7%),”

Mine doesn’t look anything like that…


#6

I have not been counting. I only am aware that my diet is high in fat, average in protein and very low in carbs.


(Bob M) #7

We’re also not genetically altered mice.


(CharleyD) #8

How’s your ALT on the Metabolic Panel? If you’re 20ish, I’d say there’s nothing to worry about.

ALT is a biomarker for degree of liver fat

https://peterattiamd.com/roblustig/


#9

following is a chart of ALT monitoring over the last 4 years. Have not had a CMP done since beginning KD 16 days ago.


(CharleyD) #10

Do the spikes correspond to illness? I like where it usually sits, but yes in this early time in your fat adaptation your liver is dusting off the beta oxidation pathways that’ve been dormant so it isn’t the most efficient thing at the moment.


#11

The spikes happened as a side effect of pharma therapy. I certainly do not want to create a new problem.


(So much bacon . . . so little time . . .) #12

I’ve corresponded with Petro Dobromylskyj, the veterinarian who writes the Hyperlipid blog (http://high-fat-nutrition.blogspot.com/), and he says it’s very difficult to get rats and mice into ketosis, hence the wildly skewed diet. Apparently, human beings are one of the very few animals to be easily able to enter nutritional ketosis. In human beings, there are many anecdotal reports of people reversing NAFLD, and some controlled studies as well. Dr. Lustig did a study on patients at his pediatric obesity clinic, and they saw great improvements in liver enzymes and reduced liver fat within one week. It is carbohydrates, particularly the fructose half of sugar (the other half being glucose, which the body can handle fairly well by secreting insulin) that causes non-alcoholic fatty liver disease, because of a process called de novo lipogenesis.


#13

I would be interested in knowing if the long timer’s have been tested for NAFLD and the results.


(Eric) #14

My alt is lower on a ketogenic diet. I had slight NAFLD and now I have no biomarkers for it. Will see in 6 more months if the trend is still my friend.


(So much bacon . . . so little time . . .) #15

I don’t intend to worry about it. Even if it’s a problem and shortens my life, I will have had a much happier time, and it will have been worth it.

Sort of like the husband and wife who die in their nineties and are being shown around Heaven by St. Peter. Seeing how great the golf course and swimming pool are, not to mention the wonderful restaurants, the husband turns to the wife and says, “You and your bran muffins and health food—we could have been here years ago!”

All the bacon I want? That’s a foretaste of Heaven already, as far as I’m concerned.