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.
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.
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.
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 []. 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 [. 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 [, . 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 [. Indeed, serum FGF21 concentrations are elevated in patients with diagnosed NAFLD, and obesity is an FGF21-resistant state [, . Fgf21 mRNA is markedly induced in livers of mice fed either KD or WD for 12 weeks [[41**].